[go: up one dir, main page]

EP0479903B1 - Substituierte imidazole und ihre verwendung als hemmmstoff fur angiotensin ii - Google Patents

Substituierte imidazole und ihre verwendung als hemmmstoff fur angiotensin ii Download PDF

Info

Publication number
EP0479903B1
EP0479903B1 EP90911154A EP90911154A EP0479903B1 EP 0479903 B1 EP0479903 B1 EP 0479903B1 EP 90911154 A EP90911154 A EP 90911154A EP 90911154 A EP90911154 A EP 90911154A EP 0479903 B1 EP0479903 B1 EP 0479903B1
Authority
EP
European Patent Office
Prior art keywords
formula
carbon atoms
compound
solvent
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP90911154A
Other languages
English (en)
French (fr)
Other versions
EP0479903A1 (de
Inventor
Robert John Ardecky
David John Carini
John Jonas Vytautas Duncia
Pancras Chor-Bun Wong
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
EIDP Inc
Original Assignee
EI Du Pont de Nemours and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by EI Du Pont de Nemours and Co filed Critical EI Du Pont de Nemours and Co
Publication of EP0479903A1 publication Critical patent/EP0479903A1/de
Application granted granted Critical
Publication of EP0479903B1 publication Critical patent/EP0479903B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/68—Halogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/84—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system

Definitions

  • This invention relates to novel substituted imidazoles, and processes for their preparation.
  • the invention also relates to pharmaceutical compositions containing the novel imidazoles, alone and in conjunction with other drugs, especially diuretics and non-steroidal anti-inflammatory drugs (NSAID's).
  • NSAID's non-steroidal anti-inflammatory drugs
  • the compounds of this invention inhibit the action of the hormone angiotensin II (AII) and are useful therefore in alleviating angiotensin induced hypertension.
  • AII angiotensin II
  • the enzyme renin acts on a blood plasma ⁇ 2-globulin, angiotensinogen, to produce angiotensin I, which is then converted by angiotensin converting-enzyme to All.
  • the latter substance is a powerful vasopressor agent which has been implicated as a causitive agent for producing high blood pressure in various mammalian species, such as the rat, dog, and man.
  • the compounds of this invention inhibit the action of AII at its receptors on target cells and thus prevent the increase in blood pressure produced by this hormone-receptor interaction.
  • a compound of this invention By administering a compound of this invention to a species of mammal with hypertension due to AII, the blood pressure is reduced.
  • the compounds of this invention are also useful for the treatment of congestive heart failure.
  • Administration of a compound of this invention with a non-steroidal anti-inflammatory drug (NSAID) can prevent renal failure which sometimes results from administration of a NSAID.
  • NSAID non-steroidal anti-inflammatory drug
  • European Published Application 0 253 310 discloses that certain substituted Imidazoles block the AII receptor and are useful therefore In alleviating angiotensin induced hypertension as well as in treating congestive heart failure.
  • the Imidazoles disclosed have the formula (I)
  • the imidazoles of the present invention differ from those of EPA 0 253 310 in the substituents R7 at positions 4 or 5 of the imidazole ring.
  • R7 and R8 are defined as follows:
  • Saralasin has been demonstrated to lower arterial pressure in mammals and man when the (elevated) pressure is dependent on circulating AII (Pals et al., Circulation Research, 29 , 673 (1971); Streeten and Anderson, Handbook of Hypertension, Vol. 5, Clinical Pharmacology of Antihypertensive Drugs, A. E. Doyle (Editor), Elsevier Science Publishers B.V., p. 246 (1984)).
  • AII circulating circulating AII
  • saralasin due to its agonistic character, saralasin generally elicits pressor effects when the pressure is not sustained by All. Being a peptide, the pharmacological effects to saralasin are relatively short-lasting and are only manifest after parenteral administration, oral doses being ineffective.
  • peptide AII-blockers like saralasin, are severely limited due to their oral ineffectiveness and short duration of action, their major utility is as a pharmaceutical standard.
  • Some known non-peptide antihypertensive agents act by inhibiting an enzyme, called angiotensin converting enzyme (ACE), which is responsible for conversion of angiotensin I to AII. Such agents are thus referred to as ACE inhibitors, or converting enzyme inhibitors (CEI's).
  • ACE inhibitors or converting enzyme inhibitors (CEI's).
  • CEI's converting enzyme inhibitors
  • Captopril and enalapril are commercially available CEI's. Based on experimental and clinical evidence, about 40% of hypertensive patients are non-responsive to treatment with CEI's. But when a diuretic such as furosemide or hydrochlorothiazide is given together with a CEI, the blood pressure of the majority of hypertensive patients is effectively normalized.
  • Diuretic treatment converts the non-renin dependent state in regulating blood pressure to a renin-dependent state.
  • the imidazoles of this invention act by a different mechanism, i.e., by blocking the All receptor rather than by inhibiting the angiotensin converting enzyme, both mechanisms involve interference with the reninangiotensin cascade.
  • a combination of the CEI enalapril maleate and the diuretic hydrochlorothiazide is commercially available under the trademark Vaseretic ® from Merck & Co. Publications which relate to the use of diuretics with CEI's to treat hypertension, in either a diuretic-first, stepwise approach or in physical combination, include Keeton, T. K. and Campbell, W.
  • Diuretics have also been administered in combination with saralasin to enhance the antihypertensive effect.
  • Non-steroidal anti-inflammatory drugs have been reported to induce renal failure in patients with renal underperfusion and high plasma level of AII. (Dunn, M.J., Hospital Practice, 19:99, 1984).
  • Administration of an AII blocking compound of this invention in combination with an NSAID can prevent such renal failure.
  • Saralasin has been shown to Inhibit the renal vasoconstrictor effect of indomethacin and meclofenamate in dogs (Satoh et al., Circ. Res. 36/37 (Suppl. I):I-89, 1975; Blasingham et al., Am. J. Physiol. 239:F360, 1980).
  • CEI captopril has been demonstrated to reverse the renal vasoconstrictor effect of indomethacin in dogs with non-hypotensive hemorrhage. (Wong et al., J. Pharmacol, Exp, Ther, 219:104, 1980).
  • novel compounds of formula (I) which have angiotensin II-antagonizing properties and are useful as antihypertensives.
  • salts include both the metallic (inorganic) salts and organic salts; a list of which is given in Remington's Pharmaceutical Sciences , 17th Edition, pg. 1418 (1985). It is well known to one skilled in the art that an appropriate salt form is chosen based on physical and chemical stability, flowability, hydroscopicity and solubility. Preferred salts of this invention for the reasons cited above include potassium, sodium, calcium and ammonium salts.
  • compositions comprising a suitable pharmaceutical carrier and a compound of Formula (I), and methods of using the compounds of Formula (I) to treat hypertension and congestive heart failure.
  • the pharmaceutical compositions can optionally contain one or more other therapeutic agents, such as a diuretic or a non-steroidal antiinflammatory drug.
  • NSAID non-steroidal antiinflammatory drug
  • the compounds of this invention can also be used as diagnostic agents to test the renin angiotensin system.
  • a radical can be a substituent in more than one previously defined radical
  • that first radical can be selected independently in each previously defined radical.
  • R1, R and R3 can each be CONHOR1.
  • R1 need not be the same substituent in each of R1, R and R3 but can be selected independently for each of them.
  • novel compounds of Formula (I) may be prepared using the reactions and techniques described in this section.
  • the reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected. It is understood by those skilled in the art of organic synthesis that the functionality present on the imidazole and other portions of the molecule must be consistent with the chemical transformations proposed. This will frequently necessitate judgment as to the order of synthetic steps, protecting groups required, deprotection conditions, and activation of a benzylic position to enable attachment to nitrogen on the imidazole nucleus. Throughout the following section, not all compounds of Formula (I) falling into a given class may necessarily be prepared by all methods described for that class. Substituents on the starting materials may be incompatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternative methods described must then be used.
  • compounds of Formula ( 3 ) can be prepared by direct alkylation onto imidazole ( 1 ), with an appropriately protected benzyl halide, tosylate or mesylate ( 2 ) in the presence of base, as shown in path a).
  • the metallic imidazolide salt is prepared by reacting imidazole ( 1 ) with a proton acceptor such as MH where M is lithium, sodium or potassium in a solvent such as dimethylformamide (DMF) or by reacting it with a metal alkoxide of formula MOR where R is methyl, ethyl, t-butyl or the like In an alcohol solvent such as ethanol or t-butanol, or a dipolar aprotic solvent such as dimethylformamide.
  • the imidazole salt is dissolved in an inert aprotic solvent such as DMF, and treated with an appropriate alkylating agent ( 2 ).
  • a base such as sodium carbonate, potassium carbonate, triethylamine or pyridine.
  • the reaction is run in an inert solvent such as DMF or DMSO at 20°C to the reflux temperature of the solvent for 1-10 hours.
  • R7 and R8 are different, mixtures of two regioisomer alkylation products ( 3b , and 3c ) are obtained in which R7 and R8 are interchanged.
  • R8 is CHO the alkylation is such that the benzyl group becomes attached to the adjacent nitrogen preferentially.
  • These isomers possess distinct physical and biological properties and can usually be separated and isolated by conventional separation techniques such as chromatography and/or crystallization.
  • any properly functionalized benzylamine derivative ( 4 ) may be converted to imine ( 6 ) by treatment with an acylamino ketone ( 5 ) in the presence of an inert solvent such as benzene, toluene, or the like, and a catalytic amount of p-toluenesulfonic acid or molecular sieves, N. Engel, and W. Steglich, Liebigs Ann. Chem. , 1916, (1978), or in the presence of alumina, F. Texier-Boulet, Synthesis , 679 (1985).
  • an inert solvent such as benzene, toluene, or the like
  • p-toluenesulfonic acid or molecular sieves such as benzene, toluene, or the like
  • the resulting imine ( 6 ) can be cyclized to the N-benzyl imidazole ( 3 ) with phosphorus pentachloride (PCl5), phosphorus oxychloride (POCl3) or triphenylphosphine (PPh3) in dichloroethane in the presence of a base such as triethylamine, N. Engel and W. Steglich, Liebigs Ann. Chem. , 1916, (1978).
  • PCl5 phosphorus pentachloride
  • POCl3 phosphorus oxychloride
  • PPh3 triphenylphosphine
  • Acylamino ketone ( 5 ) is readily obtainable from amino acids via the Dakin-West reaction, H.D. Dakin, R. West, J. Biol. Chem. , 78, 95 and 745 (1928), and various modifications thereof, W. Steglich, G. Hofle, Angew. Chem. Int. Ed. Engl. , 8 , 98l (1969); G. Hofle, W. Steglich, H. Vorbruggen, Angew. Chem. Int. Ed. Engl. , 17 , 569 (1978); W. Steglich, G. Hofle, Ber. , 102 , 883 (1969), or by selective reduction of acyl cyanides, A. Pfaltz, S. Anwar, Tet. Lett. 2977 (1984), or from ⁇ -halo, ⁇ -tosyl or ⁇ -mesyl ketones via the appropriate substitution reactions that one skilled in the art will readily recognize.
  • the functionalized benzylamines ( 4 ) may be made from the corresponding benzyl halide, tosylate or mesylate ( 2 ) via displacement with a nitrogen nucleophile, a procedure familiar to one skilled in the art. This displacement may be achieved using azide ion, ammonia, or phthalimide anion, etc., in a neutral solvent such as dimethylformamide, dimethylsulfoxide etc., or under phase transfer conditions.
  • the benzyl halide ( 2 ) may be made by a variety of benzylic halogenation methods familiar to one skilled in the art, for example benzylic bromination of toluene derivatives with N-bromosuccinimide in an inert solvent such as carbon tetrachloride in the presence of a radical initiator such as benzoyl peroxide at temperatures up to reflux conditions.
  • toluene derivatives may be made from simple electrophilic substitution reactions on an aromatic ring. This includes nitration, sulfonation, phosphorylation, Friedel-Crafts alkylation, Friedel-Crafts acylation, halogenation, and other similar reactions known to one skilled in the art, G. A. Olah, "Friedel-Crafts and Related Reactions," Vol. 1-5 , Interscience, New York, (1965).
  • the appropriately substituted benzene ring may be chloromethylated with formaldehyde and hydrochloric acid (HCl) for example with or without an inert solvent such as chloroform, carbon tetrachloride, light petroleum ether or acetic acid.
  • HCl formaldehyde and hydrochloric acid
  • a Lewis acid such as zinc chloride (ZnCl2) or a mineral acid such as phosphoric acid may also be added as a catalyst or condensing agent, R. C. Fuson, C. H. McKeever, Org. Reactions , 1 , 63 (1942).
  • N-benzylimidazoles ( 3 ) can also be prepared as shown in path b) by forming an R6 substituted amidine ( 7 ) from an appropriately substituted benzylamine ( 4 ) which is in turn reacted with an ⁇ -haloketone, ⁇ -hydroxyketone ( 8 ), ⁇ -haloaldehyde, or ⁇ -hydroxyaldehyde, F. Kunckell, Ber. , 34 , 637 (1901).
  • imidazole ( 1 ) may be alkylated by a variety of benzyl derivatives. These include compounds with latent acid functionalities such as o, m, and p-cyanobenzylhalides, mesylates or tosylates as shown in path c). Nitriles of formula ( 9 ) may be hydrolyzed to carboxylic acids of formula ( 10 ) by treatment with strong acid or alkali.
  • treatment with a l:l (v/v) mixture of concentrated aqueous hydrochloric acid/glacial acetic acid at reflux temperatures for 2-96 hours or by treatment with 1 N sodium hydroxide in an alcohol solvent such as ethanol or ethylene glycol for 2-96 hours at temperatures from 20°C to reflux can be used.
  • another nitrile group is present it will also be hydrolyzed.
  • the nitrile functionality can also be hydrolyzed in two steps by first stirring in sulfuric acid to form the amide followed by hydrolysis with sodium hydroxide or a mineral acid to give the carboxylic acid ( 10 ).
  • the nitriles ( 9 ) can be converted into the corresponding tetrazole derivative ( 11 ) by a variety of methods using hydrazoic acid.
  • the nitrile can be heated with sodium azide and ammonium chloride in DMF at temperatures between 30°C and reflux for l-10 days, J. P. Hurwitz and A. J. Tomson, J. Org. Chem. , 26 , 3392 (196l).
  • the tetrazole is prepared by the 1,3-dipolar cycloaddition of trialkyltin or triaryltin azides to the appropriately substituted nitrile as described in detail by Scheme 15 .
  • the starting imidazole compounds ( 1 ) are readily available by any of a number of standard methods.
  • acylaminoketone ( 5 ) can be cyclized with ammonia or equivalents thereof, D. Davidson, et al., J. Org. Chem. , 2 , 319 (1937) to the corresponding imidazole as shown in Scheme l .
  • the corresponding oxazole can also be converted to imidazole ( 1 ) by action of ammonia or amines in general, H. Bredereck, et al., Ber. , 88 , 1351 (1955); J. W. Cornforth and R. H. Cornforth, J. Chem Soc. , 96, (1947).
  • the starting imidazole compounds ( 1 ) wherein R7 and R8 are both hydrogen can be prepared as shown in equation b) by reaction of the appropriate R6-substituted imidate ester ( 12 ) with ⁇ -aminoacetaldehyde dimethyl acetal ( 13 ), M. R. Grimmett, Adv. Heterocyclic Chem. , 12 , 103 (1970).
  • Halogenation of imidazole ( 15 ) or any imidazole wherein R7 or R8 is hydrogen is preferably accomplished by reaction with one to two equivalents of N-halosuccinimide in a polar solvent such as dioxane or 2-methoxyethanol at a temperature of 40-100°C for 1-10 hours.
  • Compounds of formula ( 17 ) can also be prepared by treatment of the starting imidazole compound ( 1 ) wherein R7 and R8 are both hydrogen, with the appropriate benzyl halide followed by functionalization of R7 and R8 by treatment with formaldehyde as described in E. F. Godefroi, et al., Recueil , 91, 1383 (1972) followed by halogenation as was described above.
  • the imidazoles ( 1 ) can also be prepared by reaction of R6 substituted amidines ( 18 ) with an ⁇ -hydroxy- or ⁇ -haloketone or aldehyde ( 8 ) as described by F. Kunckel, Ber ., 34 , 637, (190l).
  • the hydroxymethyl groups may be easily converted to the corresponding halide, mesylate or tosylate by a variety of methods familiar to one skilled in the art.
  • the alcohol ( 17 ) is converted to the chloride ( 25 ) with thionyl chloride in an inert solvent at temperatures of 20°C to the reflux temperature of the solvent.
  • Chloride ( 25 ) may be displaced by a variety of nucleophiles by nucleophilic displacement reaction procedures familiar to one skilled in the art. For example, excess sodium cyanide in DMSO may be used to form cyanomethyl derivatives ( 26 ) at temperatures of 20°C to 100°C.
  • Nitrile ( 26 ) may be hydrolyzed to an acetic acid derivative ( 27 ), by a variety of methods. These methods include methods described previously for the hydrolysis of nitriles of formula ( 9 ). Examples of desired acids and bases for this hydrolysis include mineral acids such as sulfuric acid, hydrochloric acid, and mixtures of either of the above with 30-50% acetic acid (when solubility is a problem), and alkali metal hydroxides such as sodium hydroxide or potassium hydroxide.
  • the hydrolysis reaction proceeds under heating at temperatures ranging from 50-160°C for 2-48 hours.
  • Carboxylic acid ( 27 ) may be esterified by a variety of methods without affecting other parts of the molecule.
  • ( 27 ) is refluxed in a hydrochloric acid/methanol solution for 2-48 hours to give ester ( 28 ).
  • Ester ( 28 ) may be hydrolyzed to carboxylic acid ( 27 ), for instance, after R1, R and R3 have been elaborated.
  • carboxylic acid ( 27 ) may be hydrolyzed to carboxylic acid ( 27 ), for instance, after R1, R and R3 have been elaborated.
  • Various methods, acidic or basic, may be used.
  • compound ( 28 ) is stirred with 0.5 N potassium hydroxide in methanol, or if base soluble, it is stirred in 1.0 N sodium hydroxide for l-48 h at 20°C to reflux temperatures.
  • Hydroxymethyl derivative ( 17 ) may be acylated to give ( 29 ) by a variety of procedures. As shown in path b) acylation can be achieved with l-3 equivalents of an acyl halide or an anhydride in a solvent such as diethyl ether, tetrahydrofuran, methylene chloride or the like in the presence of a base such as pyridine or triethylamine.
  • ( 17 ) may be acylated by reaction with a carboxylic acid and dicyclohexylcarbodiimide (DCC) in the presence of a catalytic amount of 4-(N,N-dimethylamino)pyridine (DMAP) via the procedure described by A. Hassner, Tet. Lett., 46 , 4475 (1978). Treatment of ( 17 ) with a solution of carboxylic acid anhydride in pyridine optionally with a catalytic amount of DMAP at temperatures of 20-100°C for 2-48 hours is the preferred method.
  • the ether ( 30 ) can be prepared from the alcohol ( 17 ) as shown in path c) by methods such as treatment of ( 17 ) in a solvent such as dimethylformamide or dimethylsulfoxide with potassium t -butoxide, sodium hydride, or the like followed by treatment with R11L at 25°C for 1-20 hours, where L is a halogen, tosylate or mesylate.
  • a solvent such as dimethylformamide or dimethylsulfoxide with potassium t -butoxide, sodium hydride, or the like
  • R11L at 25°C for 1-20 hours, where L is a halogen, tosylate or mesylate.
  • the ether ( 30 ) can also be prepared for example by heating ( 17 ) for 3-15 hours at 60-160°C in R11OH containing an inorganic acid such as a hydrochloric acid or sulfuric acid.
  • equation a) the reaction of aniline derivative ( 34 ) with imidate ester ( 12 ) to form the substituted amidine ( 35 ) provides material which can be cyclized with dihydroxyacetone to form structure ( 36 ). Subsequent elaboration into (I) provides the N-arylimidazole compounds of the invention.
  • R1, R and R3 do not necessarily remain the same from the starting compound to the final products, but are often manipulated through known reactions in the intermediate steps as shown in Schemes 5-22 . All of the transformations shown in Schemes 5-10 and 12 can also be carried out on the terminal aromatic ring (i.e., biphenyl ring).
  • compounds where R1 is a sulfonic acid group may be prepared by oxidation of the corresponding thiol ( 45 ).
  • an N-benzylimidazole derivative bearing a thiol group may be converted into a sulfonic acid ( 46 ) by the action of hydrogen peroxide, peroxyacids such as metachloroperoxybenzoic acid, potassium permanganate or by a variety of other oxidizing agents, E. E. Reid, Organic Chemistry of Bivalent Sulfur , l , Chemical Publishing Co., New York, 120-12l (1958).
  • Aromatic hydroxy or thiol groups are obtained from deprotection of the corresponding alkyl ether or thioethers.
  • a methyl ether or a methyl thioether derivative ( 44 ) of an N-benzylimidazole containing one or more aromatic rings may be converted into the free phenol or thiophenol ( 45 ) by the action of boron tribromide methyl sulfide, P. G. Willard and C. F. Fryhle, Tet. Lett. , 21 , 373l (1980); trimethylsilyl iodide, M. E. Jung and M. A. Lyster, J. Org. Chem. , 42 , 376l (1977); KSEt and derivatives thereof, G. I. Feutrill, R. N. Mirrington, Tet. Lett. , 1327, (1970), and a variety of other reagents.
  • N-benzylimidazoles may be sulfonated by stirring with H2SO4 at a variety of different concentrations or with other sulfonating agents such as chlorosulfonic acid or sulfur trioxide with or without complexing agents such as dioxane or pyridine at temperatures from 0 to 200°C with or without solvent, K. LeRoi Nelson in Friedel-Crafts and Related Reactions, III part 2, G. A. Olah, ed., Interscience Publ., 1355 (1964).
  • N-Benzylimidazoles containing a phenolic hydroxyl group ( 47 ) may be readily converted into the corresponding sulfate ( 48 ) or phosphate ( 49 ).
  • reaction of the phenol with a sulfur trioxide-amine complex will give the corresponding sulfate ( 48 ), E. E. Gilbert, Sulfonation and Related Reactions , Interscience, New York, chapter 6 (1965).
  • Reaction of the phenol ( 47 ) with phosphorus pentachloride followed by hydrolysis will give the corresponding phosphate ( 49 ), G. M. Kosolapoff, Organophosphorus Compounds , John Wiley, New York, 235 (1950).
  • N-benzylimidazoles may be converted into the corresponding phosphonic acids by reaction with phosphorus trichloride (PCl3) and aluminum chloride (AlCl3) in an inert solvent for 0.5-96 hours from temperatures of 25°C to the reflux temperatures of the solvent.
  • PCl3 phosphorus trichloride
  • AlCl3 aluminum chloride
  • equation c) illustrates that aryl phosphonic acids ( 52 ) may be formed from reaction of the corresponding diazonium salt ( 53 ) with PCl3 in the presence of Cu(I) followed by hydrolysis with water (ibid, p. 1286).
  • the aryl halides ( 55 ) may be photolyzed in the presence of phosphite esters to give phosphonate esters ( 56 ), R. Kluger, J. L. W. Chan, J. Am. Chem. Soc. , 95 , 2362, (1973). These same aryl halides also react with phosphite esters in the presence of nickel or palladium salts to give phosphonate esters, P. Tavs, Chem. Ber. , 103 , 2428 (1970), which can be subsequently converted to phosphonic acids ( 52 ) by procedures known to one skilled in the art.
  • N-Benzylimidazoles containing an aldehyde or ketone ( 57 ) may be reacted with a phosphorus trihalide followed by water hydrolysis to give ⁇ -hydroxyphosphonic acid derivatives, G.M. Kosolapoff, op. cit. , 304, as shown in Scheme 7 .
  • R1 is -CONHOR1
  • Scheme 8 Compounds where R1 is -CONHOR1 may be prepared as shown in Scheme 8 , by the treatment of a carboxylic acid ( 10 ) with 1-4 equivalents of thionyl chloride for 1-10 hours. This reaction can be run without solvent or in a nonreactive solvent such as benzene or chloroform at temperatures of 25-65°C. The intermediate acid chloride is then treated with 2-10 equivalents of the appropriate amine derivative, H2NOR1, for 2-18 hours at temperatures of 25-80°C in a polar aprotic solvent such as tetrahydrofuran or dimethylsulfoxide to give the hydroxamic acid ( 59 ).
  • a aprotic solvent such as tetrahydrofuran or dimethylsulfoxide
  • the carboxylic acid ( 10 ) can be converted to the hydroxamic acid ( 59 ) according to the procedure in J. Med. Chem. , 28 , 1158 (1985) by employing dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, and H2NOR1 or according to the procedure described in Synthesis , 929 (1985) employing the Vilsmeier reagent and H2NOR1.
  • these acylsulfonamides ( 59a ) can be prepared from the carboxylic acids ( 10 ) through the corresponding N,N-diphenylcarbamoyl anhydrides ( 10a ) as described by F. J. Brown, et al. in Eur. Pat. Appl. EP 199543 ( see Scheme 8 ).
  • Aniline intermediates ( 63 ) are disclosed in U.S. Patent No. 4,355,040 and may be obtained from the corresponding nitro compound precursor by reduction.
  • a variety of reduction procedures may be used such as iron/acetic acid, D. C. Owsley, J. J. Bloomfield, Synthesis , 118, (1977), stannous chloride, F. D. Bellamy, Tet. Lett. , 839, (1984) or careful hydrogenation over a metal catalyst such as palladium.
  • aniline intermediates of N-benzylimidazoles may also be prepared from the corresponding carboxylic acid ( 10 ) or acid chloride via a Curtius rearrangement of an intermediate acyl azide ( 60 ). More modern methods include using diphenylphosphoryl azide as a source of azide, T. Shioiri, K. Ninomiya, S. Yamada, J. Am. Chem. Soc. , 94 , 6203 (1972), and trapping the intermediate isocyanate ( 61 ) produced by the Curtius rearrangement with 2-trimethylsilylethanol and cleaving the resultant carbamate ( 62 ) with fluoride to liberate the amine ( 63 ), T. L. Capson and C. D. Poulter, Tet. Lett. , 25 , 3515 (1984). Classical procedures familiar to one skilled in the art may also be employed.
  • Sulfonamide compounds ( 65 ) may be made by reacting an arylsulfonyl chloride ( 64 ) with ammonia, or its equivalent. Unsubstituted arylsulfonamides are made by reaction with ammonia in aqueous solution or in an inert organic solvent, F. H. Bergheim and W. Braker, J. Am. Chem. Soc. , 66 , 1459 (1944), or with dry powdered ammonium carbonate, E. H. Huntress and J. S. Autenrieth, J. Am. Chem. Soc. , 63 , 3446 (1941); E. H. Huntress and F. H. Carten, J. Am. Chem. Soc. , 62 , 5ll (1940).
  • the sulfonyl chloride precursor may be prepared by chlorosulfonation with chlorosulfonic acid on the aromatic ring directly, E. H. Huntress and F. H. Carten, ibid. ; E. E. Gilbert, op. cit. , 84, or by reacting the corresponding aromatic diazonium chloride salt ( 53 ) with sulfur dioxide in the presence of a copper catalyst, H. Meerwein, et al., J. Prakt. Chem. , [ii], 152 , 25l (1939), or by reacting the aromatic sulfonic acid ( 46 ) with PCl5 or POCl3, C. M. Suter, The Organic Chemistry of Sulfur , John Wiley, 459 (1948).
  • Linked ester compounds of formula (I) where R1 is can be made by procedures well known in penicillin and cephalosporin chemistry. The purpose is to provide materials which are more lipophilic and which will be useful orally by rapid transit from the gut into the bloodstream, and which will then cleave at a sufficiently rapid rate to provide therapeutically useful concentrations of the active carboxylic acid form.
  • the following review articles and references cited therein discuss this concept and the chemistry involved in preparing such compounds V. J. Stella, et al., Drugs , 29 , 455-473 (1985); H. Ferres, Drugs of Today . 19 (9), 499-538 (1983); A. A. Sirkula, Ann. Repts. Med. Chem. , 10 , 306-315 (1975).
  • Hexafluoroisopropanol compounds ( 72 ) may be prepared by treatment of arylsilane ( 71 ) with 1-5 equivalents of hexafluoroacetone in a solvent such as methylene chloride at temperatures ranging from about -50° to 25°C for a period of 2-10 hours.
  • a solvent such as methylene chloride
  • the requisite arylsilane ( 71 ) can be prepared using methods known to one skilled in the art such as the procedures described in Chapter 10 of Butterworth's "Silicon in Organic Chemistry".
  • compound ( 73 ) may be obtained by reacting aniline ( 63 ) with the requisite acid chloride by either a Schotten-Baumann procedure, or simply stirring in a solvent such as methylene chloride in the presence of a base such as sodium bicarbonate, pyridine, or triethylamine.
  • aniline ( 63 ) may be coupled with an appropriate carboxylic acid via a variety of amide or peptide bond forming reactions such as DCC coupling, azide coupling, mixed anhydride synthesis, or any other coupling procedure familiar to one skilled in the art.
  • Aniline derivatives ( 63 ) will undergo reductive amination with aldehydes and ketones to form secondary amines ( 74 ).
  • the aniline is first stirred with the carbonyl compound in the presence of a dehydration catalyst such as molecular sieves or p-toluenesulfonic acid. Afterwards the resultant imine is reduced to the amine with a borohydride reducing agent such as sodium cyanoborohydride or sodium borohydride.
  • Standard catalytic hydrogenation reagents such as hydrogen and palladium/carbon can also be employed.
  • aniline ( 63 ) may be monoalkylated by reaction with ethyl formate followed by reduction with, for example, lithium aluminum hydride to produce the N-methyl derivative ( 74 ).
  • maleic anhydride, 2,3-naphthalenedicarboxylic acid anhydride, and diphenic anhydride are reacted in a similar fashion to phthalic anhydride with aniline ( 63 ) or ( 74 ) to yield carboxylic acids ( 76 ), ( 77 ), and ( 78 ), respectively.
  • Phthalimide derivatives of aniline ( 63 ) may be made by a variety of methods, preferably by stirring aniline ( 63 ) with phthalic anhydride in acetic acid at a temperature between 20°C and reflux, G. Wanag, A. Veinbergs, Ber ., 75 , 1558 (1942), or by stirring ( 63 ) with phthaloyl chloride, a base such as triethylamine, and an inert solvent.
  • Aniline ( 63 ) may be converted into its trifluoromethanesulfonamide derivative or its trifluoroacetamido derivative preferably by reacting it with triflic anhydride or trifluoroacetic anhydride and a base such as triethylamine in an inert solvent such as methylene chloride at -78°C followed by warming to room temperature.
  • Equation a) illustrates that the biphenyl compounds ( 80 ) can be prepared by alkylation of imidazole ( 1 ) with the appropriate halomethylbiphenyl compound ( 79 ) by the general procedure described in Scheme 1 .
  • halomethylbiphenyl intermediates ( 79 ) are prepared by Ullman Coupling of ( 81 ) and ( 82 ) as described in "Organic Reactions", 2 , 6 (1944) to provide intermediates ( 83 ), which are in turn halogenated.
  • Halogenation can be accomplished by refluxing ( 83 ) in an inert solvent such as carbon tetrachloride for 1-6 hours in the presence of a N-halosuccinimide and an initiator such as azobisisobutyronitrile (equation b).
  • derivatives of intermediate ( 83 ) in which R13 is at the 2' position ( 83a ) can also be prepared by the method described in J. Org. Chem. , 41 , 1320 (1976), that is Diels-Alder addition of a 1,3-butadiene to a styrene ( 84 ) followed by aromatization of intermediate ( 85 ).
  • nickel-catalyzed cross-coupling of an arylzinc halide with a halobenzonitrile yields a biphenylnitrile which can in turn be hydrolyzed by standard methods to afford acid 88 .
  • the substituted biphenyl tetrazoles ( 83 ; where can be prepared from the nitrile precursors (R13 CN) by the methods described in Scheme 1 , equation c) and Scheme 15 , equation c).
  • the trialkyl or triaryltin group is removed via acidic or basic hydrolysis and the tetrazole can be protected with the trityl group by reaction with trityl chloride and triethylamine to give ( 91 ).
  • Bromination as previously described herein with N-bromosuccinimide and dibenzoylperoxide affords compound ( 92 ).
  • protecting groups such as p-nitrobenzyl and 1-ethoxyethyl can be used instead of the trityl group to protect the tetrazole moiety.
  • These groups as ll as the trityl group can be introduced and removed by procedures described in Greene, Protective Groups in Organic Synthesis , Wiley-Interscience, (1980).
  • the halomethyldiphenyl ether ( 109 ) employed as an alkylating agent in the present invention is prepared as shown in equation b).
  • An Ullman ether condensation of the phenol ( 97 ) and a halobenzoic acid as described in Russian Chemical Reviews , 43 , 679 (1974) provides the intermediate acid ( 101 ).
  • the conversion of ( 101 ) into ( 109 ) is accomplished by esterification with diazomethane to afford ( 105 ) followed by halogenation employing the procedure used in the preparation of ( 79 ).
  • the diphenylsulfide ( 110 ) and the diphenylamine ( 111 ) can be prepared from the appropriate thiophenol ( 98 ) or aniline ( 99 ) by this procedure.
  • the tertiary diphenylamine ( 112 ) can be prepared from the secondary aniline ( 100 ) by the above procedure.
  • ( 107 ) can be alkylated by one of the following procedures: 1) direct alkylation of ( 107 ) with R6L where L is a leaving group such as a halogen or tosylate employing phase-transfer conditions and ultrasound as described in Tetrahedron Letters, 24 , 5907 (1983), 2) treatment of ( 107 ) with 1-1.5 equivalents of an appropriate aldehyde and 0.5-5.0 equivalents of sodium cyanoborohydride in a solvent such as methanol at 25°C at a pH of 3-6 for 1-24 hours, or 3) reductive amination of ( 107 ) employing an appropriate carboxylic acid and sodium borohydride as described in J. Am. Chem. Soc. , 96 , 7812 (1974).
  • the tertiary amine ( 108 ) is then halogenated by the procedure
  • esters ( 113 ) where R13 is 2-CO2CH3 are prepared by alkylation of imidazole ( 1 ) with carbomethoxybenzoyl benzyl halide ( 114 ).
  • Ester ( 113 ) may be hydrolyzed to the corresponding carboxylic acid ( 116 ) by a variety of methods including hydrolysis with a base such as sodium hydroxide or potassium hydroxide in an alcoholic aqueous solvent such as methanol/H2O at a temperature from 20°C to the reflux temperature of the solvent.
  • Carboalkoxybenzoylbenzyl halides are prepared by benzylic halogenation of the corresponding toluoylbenzene precursor by a variety of methods previously described herein.
  • methyl 2-(4-methylbenzoyl)benzoate ( 115 ) can be refluxed for 2-48 hours with N-bromosuccinimide, benzoyl peroxide and carbon tetrachloride to effect benzylic bromination.
  • These alcohols may be acylated by a variety of anhydrides or acid halides in the presence of a base with or without solvent to give the corresponding esters ( 122 ).
  • the alcohols ( 120 ) may be converted into their corresponding ethers ( 123 ) by reaction of tile metal alkoxide with an alkyl halide, mesylate or tosylate in the appropriate solvent or by treatment with a mineral acid in an alcoholic solvent, or by reaction of the alcohol with diazomethane as described in G. Hilgetag and A. Martini, "Preparative Organic Chemistry", John Wiley, New York, 355-368 (1972).
  • hydrolysis of benzyl ether ( 124 ) or methyl ether ( 125 ) affords hydroxy compound ( 126 ) which can be alkylated with the appropriate benzyl halide to give ( 127 ).
  • the hydrolysis step can be effected by heating the ether at temperatures of 50°-150°C for 1-10 hours in 20-60% hydrobromic acid, or heating at 50°-90°C in acetonitrile with 1-5 equivalents of trimethylsilyl iodide for 10-50 hours followed by treatment with water.
  • Hydrolysis can also be carried out by treatment with 1-2 equivalents of boron tribromide in methylene chloride at 10°-30°C for 1-10 hours followed by treatment with water, or by treatment with an acid such as aluminum chloride and 3-30 equivalents of a sulfur-containing compound such as thiophenol, ethanedithiol, or dimethyl disulfide in methylene chloride at 0-30°C for 1-20 hours followed by treatment with water.
  • hydrolysis can be accomplished by refluxing in trifluoroacetic acid for 0.2-1 hours or by catalytic hydrogenolysis in the presence of a suitable catalyst such as 10% palladium on carbon.
  • the sulfide ( 129 ) can be prepared from the thiophenol ( 45 ) by the procedure described above to prepare the ether ( 127 ) from the phenol ( 126 ).
  • the thiophenol ( 45 ) can be prepared for example by treatment of the benzylsulfide ( 128 ) with sodium in liquid ammonia.
  • the amine ( 130 ) can be prepared as shown in equation c , from the aniline ( 63 ), itself available from reduction of the corresponding p-nitro compound ( 3a ) which has previously been described.
  • the reductive amination can be carried out by the same procedure as described in Scheme 13 for the preparation of compound ( 74 ).
  • the cis or trans stilbene ( 132 ) can be obtained by employing a Wittig reaction between the aldehyde ( 57 ) and the phosphorane ( 131 ).
  • the stilbene ( 132 ) can readily be converted to the saturated derivative ( 133 ) for example by catalytic hydrogenation employing a heterogeneous catalyst such as palladium/carbon or platinum/carbon or alternatively with a homogeneous catalyst such as tristriphenylphosphine rhodium chloride.
  • a heterogeneous catalyst such as palladium/carbon or platinum/carbon
  • a homogeneous catalyst such as tristriphenylphosphine rhodium chloride.
  • the reduction is performed in a solvent such as benzene, tetrahydrofuran or ethanol at 25°C under 1-3 atmospheres of hydrogen for 1-24 hours.
  • the cyclopropane ( 134 ) can be prepared by treating the stilbene ( 132 ) with the Simmons-Smith reagent as described in J. Am. Chem. Soc. , 81 , 4256 (1959), or by treating ( 132 ) with methylene diiodide and copper powder as described in J. Am. Chem. Soc. , 101 , 2139 (1979), or by treatment with the iron-containing methylene-transfer reagent described in J. Am. Chem. Soc. , 101 , 6473 (1979).
  • Vinylene fluorides ( 137 ) and ( 140 ) can be prepared by reaction of SF4 or Et2NSF3 (DAST) with the appropriate ketone ( 135 ) or ( 138 ) in which Ar bears a methyl group convertible to a benzylic halide suitable for attachment to an imidazole nitrogen, and Ar' bears a cyano, nitro, ester, or other suitable group which can be subsequently converted to CO2H, NHSO2CF3, etc.
  • DAST Et2NSF3
  • the initially formed difluoroethylene ( 136 ) and ( 139 ) can be formed in a non-polar solvent such as methylene chloride and subsequently converted to the vinylene fluoride by means of alumina, or converted directly into the unsaturated fluoride by running the reaction in a polar solvent such as tetrahydrofuran, diglyme or N-methylpyrrolidone in the presence of mineral acid.
  • a non-polar solvent such as methylene chloride
  • a polar solvent such as tetrahydrofuran, diglyme or N-methylpyrrolidone in the presence of mineral acid.
  • an appropriate benzoin ( 141 ) may be similarly converted to the corresponding 1,2-difluorostilbene ( 143 ).
  • an appropriate benzil ( 144 ) can be converted to a tetrafluorodiarylethylene ( 145 ) using DAST or SF4.
  • acid ( 10 ) can be made by alkylating the appropriate imidazole with methyl 4-chloromethylbenzoate in the presence of a base such as potassium carbonate in a polar solvent such as dimethylformamide followed by hydrolysis of the resulting ester.
  • Compound ( 10 ) can be converted to ( 148 ) by reaction with the requisite amine ( 146 ) (R13 may need to be protected and subsequently deprotected) and dicyclohexyl carbodiimide (DCC) in methylene chloride [J. R. Beek, et al., J. Am. Chem. Soc , 90 , 4706 (1968)] or by reaction with tosyl chloride in pyridine [J. H.
  • Yet another process involves conversion of carboxylic acid ( 10 ) to its acid chloride with, for example, thionyl chloride followed by reaction with the amine in aqueous base (Schotten-Baumann conditions) or in an organic solvent in the presence of an acid scavenger such as NaHCO3, pyridine or triethylamine, or by other procedures known to form an amide bond between an aromatic acid and an amine.
  • carboxylic acid ( 10 ) to its acid chloride with, for example, thionyl chloride followed by reaction with the amine in aqueous base (Schotten-Baumann conditions) or in an organic solvent in the presence of an acid scavenger such as NaHCO3, pyridine or triethylamine, or by other procedures known to form an amide bond between an aromatic acid and an amine.
  • a suitable protecting group however modifications necessary because of specific functional groups are understood to be incorporated by one skilled in the art of organic synthesis.
  • the alcohol ( 150 ) can be converted to the corresponding halide with SOCl2, (COCl)2, etc, and the resulting halide can then be reacted with a phenol, thiophenol or aniline in the presence of base to form the desired compound, where X is -CH2O-, -CH2S-, -CH2NH- respectively.
  • sulfonylchloride derivative ( 157 ) can be reacted with aniline derivative ( 158 ) in a solvent in the presence of an acid scavenger such as sodium bicarbonate, triethylamine or pyridine or under Schotten-Baumann like conditions to give ( 159 ).
  • an acid scavenger such as sodium bicarbonate, triethylamine or pyridine or under Schotten-Baumann like conditions.
  • Sulfonylchloride derivative ( 157 ) can be obtained by sulfonation of the corresponding benzyl derivative as described earlier, followed by reaction with PCl5 or POCl3.
  • aniline ( 74 ) may be reacted in the same manner as described above with sulfonylchloride derivative ( 160 ) to give ( 161 ).
  • Scheme 24 shows the preparation of furan analogs of the biphenyl compounds ( 80 ).
  • the alkene moiety of ( 163 ) can be subsequently cleaved by oxidation, for example, with osmium tetroxide, Fieser and Fieser, V.1, p. 812 (Lemleux-Johnson oxidation) to yield dicarbonyl-containing compound ( 164 ).
  • a variety of protecting groups may be used in the manipulation of the above triazoles, amongst which is the trityl group.
  • This group may be easily attached by reaction of the triazole with triphenylmethyl bromide or chloride in an inert solvent such as methylene chloride in the presence of an acid scavenger such as triethyl amine.
  • the trityl group may be later removed by stirring or refluxing in an acidic medium such as trifluoroacetic acid/water, HCl in methylene chloride, or acetic acid/water.
  • the trityl group may also be hydrogenolyzed using a noble metal catalyst such as palladium and hydrogen.
  • Amide ( 187 ) is converted to amidrazone ( 188 ) by reaction with PCl5 or phosgene to make an iminoyl chloride which then in turn is reacted with excess hydrazine.
  • Amidrazone ( 188 ) is cyclized to the trifluoromethyl-1,2,4-triazole ( 189 ) with trifluoroacetic anhydride and then converted to 190 via bromination, alkylation and deprotection as previously described.
  • Pertinent R6 groups may be variously introduced by many procedures including those described in Scheme 28 which describes imidazole construction.
  • R6 groups so introduced may stand unchanged or may be further elaborated if appropriately functionalized, according to methods familiar to those skilled in the art such as are illustrated in Scheme 28 .
  • the 2-alkenylimidazoles ( 201 ) can be prepared by bromination of the 2-alkylimidazoles ( 199 ) followed by elimination of hydrogen bromide.
  • the bromination is preferably accomplished by UV-irradiation for 1-4 hours of imidazole ( 199 ) and N-bromosuccinimide, in an inert solvent, such as carbon tetrachloride at 25°C.
  • Cis alkenyl derivatives (203) are prepared from the trans alkenyl compounds by treatment with osmium tetroxide and sodium periodate to afford aldehydes ( 202 ) followed by Wittig reaction.
  • R6 groups may be introduced by metallation of a protected imidazole or protected 2-methylimidazole followed by addition of an appropriate electrophile as illustrated in Scheme 30 , equations a ) and b ).
  • the products (alcohols, esters, halides, aldehydes, alkyls) are suitable for further elaboration by methods familiar to those skilled in the art.
  • Metallation of imidazoles is described in K.L. Kirk, J. Org. Chem. , 43 , 4381 (1978); R.J. Sundberg, J. Het. Chem. , 14 , 517 (1977); J.V. Hay et al., J. Org. Chem. , 38 , 4379 (1973); B. Iddon, Heterocycles , 23 , 417 (1985).
  • Various 2-substituted imidazoles can be prepared by reaction of a protected 2-trimethylsilylimidazole with a suitable electrophile by the method described by F.H. Pinkerton and S.F. Thames, J.Het. Chem. , 9 , 67 (1972), which can be further elaborated as desired.
  • R6 may also be introduced by nickel catalyzed cross-coupling of Grignard reagents with 2-(methylthio)imidazoles ( Scheme 31 ) as described by E. Wenkert and T.W. Ferreira, J. Chem. Soc. , Chem. Commun. , 840, (1982); E. Wenkert et al., J. Chem. Soc.
  • the hydroxymethyl group can be activated for the displacement reaction by reacting with thionyl chloride, PCl5 or with carbon tetrachloride/triphenylphosphine to form a corresponding chloro derivative.
  • thionyl chloride PCl5 or with carbon tetrachloride/triphenylphosphine to form a corresponding chloro derivative.
  • bromo and iodo derivatives can be obtained.
  • the hydroxymethyl group can also be activated by forming the corresponding p-toluenesulfonate, methanesulfonate and trifluoromethane sulfonate derivatives.
  • the hydroxyl group can be converted to thiolacetic acid derivative ( 215 ), J. Y. Gauthier, Tet. Lett. , 15 (1986), and to thiol derivative ( 216 ) by subsequent hydrolysis.
  • the hydroxymethyl group on compound ( 17 ) can be readily oxidized to an aldehyde group by means of manganese dioxide or ceric ammonium nitrate.
  • the aldehyde group will undergo chain extension reactions such as the Wittig and Wittig-Horner reactions and enter into typical carbon-carbon bond forming reactions with Grignard and lithium reagents as well as with compounds bearing activated methylene groups.
  • the hydroxymethyl group can be oxidized directly to an acid functionality which can in turn be converted to ester and amide derivatives.
  • the esters and amides can be prepared directly from the aldehydes by manganese dioxide oxidation in the presence of sodium cyanide and an alcohol or amine, J. Am. Chem. Sec. , 90, 5616 (1968) and J. Chem. Soc. (C), 2355 (1971).
  • the chlorine on compound ( 25 ) can be displaced by the anion of dialkyl malonate to give the corresponding malonate derivative ( 217 ).
  • the saponification of ( 217 ) with NaOH (or KOH) gives the corresponding diacid which can be decarboxylated to give the corresponding propionic acid derivative ( 218 ) by heating to 120°C.
  • ( 218 ) can be directly obtained by refluxing ( 217 ) with a mineral acid such as HCl or sulfuric acid.
  • the free acid ( 218 ) can be esterified by heating in a medium of the various alcohols and a catalytic amount of mineral acids such as HCl or sulfuric acid to give the corresponding esters ( 219 ).
  • esters can be obtained by reacting the free acid ( 218 ) and the corresponding alcohols in the presence of coupling reagents such as DDQ or EEDQ.
  • a similar reaction with various mono-substituted and disubstituted amines produces the corresponding amides ( 220 ).
  • a similar reaction with various mercaptans produces the corresponding thioesters.
  • the chloro group on ( 25 ) can be displaced by the sodium salt or potassium salt of the alkyl, aryl or arylalkyl mercaptans to give the corresponding sulfide derivatives ( 221 ).
  • the amine derivative ( 222 ) can be obtained by treating ( 25 ) with ammonia or with the corresponding mono-substituted amines.
  • the chloro group may be displaced by sodium azide to give an azide intermediate which upon reduction with H2 over a noble metal catalyst or with a reducing agent such as chromous chloride (W. K. Warburton, J. Chem. Soc. , 2651 (1961)) yields ( 222 ) where R10 and R11 are hydrogen.
  • This amine can be subsequently alkylated with alkyl halides, or reductively alkylated with aldehydes and ketones to give alkyl derivatives of ( 222 ).
  • the amines ( 222 ) are converted to the corresponding carbamates ( 224 ), sulfonamides ( 225 ), amides ( 226 ) or ureas ( 227 ) by standard procedures illustrated in Scheme 34 and familiar to one skilled in the art.
  • ester 234 may be obtained by direct oxidation of aldehyde 233 with NaCN, MnO2 in methanol (Corey, E. J., et al. J. Am. Chem. Soc. (1968) 90 , 5616). Oxidation of 233 with NaCN, MnO2, and an amine in 2-propanol leads to the corresponding amide 235 (Gilman, N. W. Chem. Comm. (1971) 733).
  • Aldehyde 233 may be made from the corresponding alcohol 17 by a variety of methods familiar to one skilled in the art, including pyridium chlorochromate (PCC), Swern and ceric ammonium nitrate (CAN) oxidations.
  • PCC pyridium chlorochromate
  • Swern Swern
  • ceric ammonium nitrate CAN
  • a transition metal catalyst such as palladium, nickel, platinum, zirconium, etc.
  • an imidazole metal derivative 239 can be coupled to an arylhalide to prepare 238 (Scheme 38b).
  • Compounds 241 may be prepared, as described in Scheme 38d, by the coupling of an alkenyl- or alkylnylmetal derivative (AM) or the corresponding alkene or alkyne (AH) with 237 .
  • AM alkenyl- or alkylnylmetal derivative
  • AH alkene or alkyne
  • 2-Alkylimidazole-4,5-dicarboxylic acids ( 242 ), prepared by the method of R.G. Fargher and F.L. Pyman (J. Chem. Soc., (1919) 115 , 217), can be converted into their corresponding diesters ( 243 ) by simply refluxing in an alcohol solvent in the presence of an acid such as HCl, or by many other methods familiar to one skilled in the art.
  • Diester ( 243 ) can then be converted into its metallic salt by reaction with sodium methoxide, sodium ethoxide, sodium hydride, potassium hydride or any other base in an appropriate solvent such as DMF.
  • the resultant salt is then alkylated with the appropriately substituted benzyl derivative ( 2 ) to yield benzylimidazole ( 244 ).
  • the above alkylation sequence may be also performed by heating or refluxing the benzyl halide (tosylate or niesylate) ( 2 ) with imidazole ( 243 ) in a solvent such as DMF in the presence of an acid scavenger such as potassium or sodium carbonate.
  • Diester ( 244 ) can be reduced with lithium aluminum hydride in an inert solvent such as THF to the corresponding dialcohol ( 245 ).
  • Selective oxidation of dialcohol ( 245 ) with manganese dioxide in an inert solvent such as THF yields primarily aldehyde ( 247 ) with a minor product dialdehyde ( 246 ).
  • Imidazoles represented by structure ( 251 ) where X is Cl, Br, or I and E is an electron withdrawing group such as an ester, ketone, nitro, alkylsulfonyl, arylsulfonyl, etc., can undergo the nucleophilic aromatic substitution reaction (H. Schubert, H. Simon, A. Jumar, Z. Chem. (1968) 62-63) where the leaving group X is substituted by a nucleophile such as sulfur, carbon, or nitrogen to yield adducts ( 252 ) (Scheme 40).
  • the reaction can be done in hydroxylic solvent such as methanol or non-hydroxylic solvent such as DMSO at room temperature to the reflux temperature of the solvent.
  • nucleophile sometimes must be converted into its anion to make it more nucleophilic.
  • thiophenol can be refluxed in methanol in the presence of sodium methoxide and the haloimidazole ( 251 ).
  • Other nucleophiles include other alkyl and arylthiols, heteroarylthiols, thiolacetic acid, alkyl and arylsulfonamides, heteroarylsulfonamides, diacylamines, alkyl and arylamines, heteroarylamines, etc., familiar to one skilled in the art.
  • the resultant sulfides can be oxidized to the corresponding sulfoxides and sulfones by methods familiar to one skilled in the art.
  • Part B Preparation of 4-Methyl-2'-(N-triphenylmethyl-(1H-tetrazol-5-yl))biphenyl
  • n-BuLi 2.5 M in THF
  • methyltriphenylphosphonium bromide 1.53 g, 4.3 mmol, 2.1 eq
  • the solvent was removed in vacuo and the residue dissolved in water (50 mL).
  • the pH was adjusted to 10-12 with 10 N NaOH.
  • Gummy solids (trityl group-containing compound) formed which were dissolved by the addition of ethyl ether (50 mL).
  • the layers were separated and the aqueous layer extracted with ethyl ether (2 x 50 mL).
  • the aqueous layer was then extracted with ethyl acetate (6 x 50 mL).
  • the ethyl acetate layers were collected, dried (MgSO4), and the solvent removed in vacuo to yield a residue which was redissolved in water (50 mL).
  • the pH was adjusted to 1 with conc. HCl.
  • Examples 243-253 in Table 7 can be made by procedures described in example 242 and other examples in this patent application and in EP 89100144.8 (published 7.19.89) or by other methods familiar to one skilled in the art.
  • AII angiotensin II
  • a ligand-receptor binding assay was utilized for the initial screen. The assay was carried out according to the method described by [Glossmann et al., J. Biol. Chem. , 249 , 825 (1974)], but with some modifications.
  • the reaction mixture contained rat adrenal cortical microsomes (source of AII receptor) in Tris buffer and 2 nM of 3H-AII with or without potential AII antagonist.
  • the potential antihypertensive effects of the compounds of this invention may be demonstrated by administering the compounds to awake rats made hypertensive by ligation of the left renal artery [Cangiano et al., J. Pharmacol. Exp. Ther. , 208 , 310 (1979)]. This procedure increases blood pressure by increasing renin production with consequent elevation of AII levels.
  • Compounds are administered orally at 30 mg/kg and/or intravenously via a cannula in the jugular vein at 3 mg/kg.
  • Arterial blood pressure Is continuously measured directly through a carotid artery cannula and recorded using a pressure transducer and a polygraph. Blood pressure levels after treatment are compared to pretreatment levels to determine the antihypertensive effects of the compounds which were tested.
  • Some compounds of this invention exhibited intravenous activity at 3 mg/kg and some exhibited oral activity at 30 mg/kg (Table 8).
  • the compounds of this invention can be administered for the treatment of hypertension according to the invention by any means that effects contact of the active ingredient compound with the site of action in the body of a warm-blooded animal.
  • administration can be parenteral, i.e., subcutaneous, intravenous, intramuscular, or intra peritoneal.
  • administration can be by the oral route.
  • the compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds.
  • the dosage administered will be dependent on the age, health and weight of the recipient, the extent of disease, kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired.
  • a dally dosage of active ingredient compound will be from about 1-500 milligrams per day. Ordinarily, from 10 to 100 milligrams per day in one or more applications is effective to obtain desired results.
  • These dosages are the effective amounts both for treatment of hypertension and for treatment of congestive heart failure, i.e., for lowering blood pressure and for correcting the hemodynamic burden on the heart to relieve the congestion.
  • the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs syrups, and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.
  • Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • parenteral solutions In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and If necessary, buffer substances.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
  • citric acid and its salts and sodium EDTA are also used.
  • parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propylparaben, and chlorobutanol.
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences , A. Osol, a standard reference text in this field.
  • Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:
  • a large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
  • a mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient.
  • the capsules are washed and dried.
  • a large number of tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose.
  • Appropriate coatings may be applied to increase palatability or delay absorption.
  • a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol. The solution is made to volume with water for injection and sterilized.
  • An aqueous suspension is prepared for oral administration so that each 5 milliliters contain 100 milligrams of finely divided active ingredient, 100 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 milliliters of vanillin.
  • the same dosage forms can generally be used when the compounds of this invention are administered stepwise in conjunction with another therapeutic agent.
  • the dosage form and administration route should be selected for compatibility with both drugs. Suitable dosages, dosage forms and administration routes are illustrated in the following tables.
  • NSAID's that can be combined with AII blockers of this invention :
  • Drug Dose (mg) Formulation Route Indomethacin 25 Tablet Oral (2/3 times daily) Meclofenamate 50-100 Tablet Oral (2/3 times daily) Ibuprofen 300-400 Tablet Oral (3/4 times daily) Piroxicam 10-20 Tablet Oral (1/2 times daily) Sulindac 150-200 Tablet Oral (2 times daily) Azapropazone 200-500 Tablet Oral (3/4 times daily)
  • diuretics examples include Drug Dose (mg) Formulation Route Benzothiadizides 25-100 (daily) Tablet Oral (e.g. hydrochlorothiazide) Loop diuretics 50-80 (daily) Tablet Oral (e.g. furosemide)
  • the dosage of AII blockers will generally be the same as when the AII blocker is used alone, i.e., 1-500 milligrams per day, ordinarily from 10 to 100 milligrams per day in one or more applications.
  • the initial dose of All blocker can be less, e.g., 1-100 milligrams per day and for the more active compounds 1-10 milligrams per day.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • External Artificial Organs (AREA)
  • Seal Device For Vehicle (AREA)
  • Nonmetallic Welding Materials (AREA)

Claims (58)

  1. Verfahren zur Herstellung einer blutdrucksenkenden Verbindung der Formel
    Figure imgb0354
     worin
    R¹   4-CO₂H; 4-CO₂R⁹;
    Figure imgb0355
     -SO₃H ; -C(CF₃)₂OH ;
    Figure imgb0356
     -PO₃H₂ ;
    Figure imgb0357
     4-NHSO₂CH₃ ; 4-NHSO₂CF₃ ; -CONHOR12; -SO₂NH₂;
    Figure imgb0358
    Figure imgb0359
    Figure imgb0360
     4-CONHNHSO₂CF₃;
    Figure imgb0361
    Figure imgb0362
     oder
    Figure imgb0363
     ist,
    R   H, Cl, Br, I, F, NO₂, CN, Alkyl mit 1 bis 4 Kohlenstoffatomen, Acyloxy mit 1 bis 4 Kohlenstoffatomen, Alkoxy mit 1 bis 4 Kohlenstoffatomen, CO₂H, CO₂R⁹, NHSO₂CH₃, NHSO₂CF₃, CONHOR¹, SO₂NH₂,
    Figure imgb0364
     Phenyl oder Furyl ist,
    R³   H, Cl, Br, I oder F, Alkyl mit 1 bis 4 Kohlenstoffatomen oder Alkoxy mit 1 bis 4 Kohlenstoffatomen ist,
    R⁴   CN, NO₂ oder CO₂R¹¹ ist,
    R⁵   H, Alkyl mit 1 bis 6 Kohlenstoffatomen, Cycloalkyl mit 3 bis 6 Kohlenstoffatomen, Alkenyl oder Alkinyl mit 2 bis 4 Kohlenstoff ist,
    R⁶   Alkyl mit 2 bis 10 Kohlenstoffatomen, Alkenyl oder Alkinyl mit 3 bis 10 Kohlenstoffatomen oder dieselben, durch F oder CO₂R¹⁴ substituierten Gruppen, Cycloalkyl mit 3 bis 8 Kohlenstoffatomen, Cycloalkylalkyl mit 4 bis 10 Kohlenstoffatomen, Cycloalkylalkenyl oder Cycloalkylalkinyl mit 5 bis 10 Kohlenstoffatomen, gegebenenfalls durch F oder CO₂R¹⁴ substituiertes (CH₂)sZ(CH₂)mR⁵, Benzyl oder im Phenylring durch 1 oder 2 Halogene, Alkoxy mit 1 bis 4 Kohlenstoffatomen, Alkyl mit 1 bis 4 Kohlenstoffatomen oder Nitro substituiertes Benzyl ist,
    R⁷   Vinyl, Cycloalkylidenyl, Alkinyl mit 2-10 Kohlenstoffatomen, Phenylalkinyl, worin der Alkinylteil 2-6 Kohlenstoffatome darstellt, aus 2- und 3-Thienyl, 2- und 3-Furyl, 2-, 3- und 4-Pyridyl, 2-Pyrazinyl, 2-, 4- und 5-Pyrimidinyl, 3- und 4-Pyridazinyl, 2-, 4- und 5-Thiazolyl, 2-, 4- und 5-Selenazolyl und 2-, 4- und 5-Oxazolyl, 2- oder 3-Pyrrolyl, 3-, 4- oder 5-Pyrazolyl, 2-, 4- oder 5-Imidazolyl ausgewähltes Heteroaryl, o-, m- oder p-Biphenylyl, o-, m- oder p-Phenoxyphenyl, 2-Oxazolinyl, 2-Thiazolinyl, substituiertes, vorstehend definiertes Phenylalkinyl, Heteroaryl, Biphenylyl oder Phenoxyphenyl, das durch 1 oder 2 Substituenten substituiert ist, die aus Halogen, Hydroxy, Mercapto, Alkoxy mit 1-5 Kohlenstoffatomen, Alkyl mit 1-5 Kohlenstoffatomen, -NO₂, -CN, -CF₃, -COR¹⁶, -CH₂OR¹⁷, -NHCOR¹⁷, -CONR¹⁸R¹⁹, S(O)rR¹⁷ und SO₂NR¹⁸R¹⁹ ausgewählt sind, vorstehend definiertes Pyrrolyl, Pyrazolyl oder Imidazolyl, das am Ringstickstoff durch Alkyl mit 1-5 Kohlenstoffatomen, Phenyl oder Benzyl substituiert ist, oder substituiertes Alkyl, Alkenyl oder Alkinyl mit 1 bis 10 Kohlenstoffatomen ist, das durch eine substituierte oder unsubstituierte, vorstehend definierte Heteroaryl-, Biphenylyl- oder Phenoxyphenylgruppe, -S(O)r-Heteroaryl, -S-(O)r-Biphenylyl, -S (O)r-Phenoxyphenyl, -S-Tetrazol, -S(O)rR¹⁷, -NR¹⁸R¹⁹, -NR¹⁸-Heteroaryl, -NR¹⁸-Phenyl, -NR¹⁸-Biphenylyl, -NR¹⁸-Phenoxyphenyl, -N-Phthalimido, -NH-SO₂-Phenoxyphenyl, -NH-SO₂-Heteroaryl, -NH-SO₂-Biphenylyl, -NH-SO₂-R¹⁷ und -S-(C=O)-R¹⁷, -N-Imidazolyl, N-1,2,3-Triazolyl, N-1,2,4-Triazolyl substituiert ist, worin Heteroaryl ein im Umfang von R⁷ definierter Heterocyclus ist und worin die Phenylgruppe in R¹⁷ von -S-(O)rR¹⁷, N-Imidazolyl, N-1,2,3-Triazolyl und N-1,2,4-Triazolyl durch einen oder zwei vorstehend für Heteroaryl beschriebene Substituenten substituiert sein können,
    R⁸   
    Figure imgb0365
     -(CH₂)nSR¹⁵;
    Figure imgb0366
    Figure imgb0367
     -(CH₂)m-Tetrazolyl;
    Figure imgb0368
    Figure imgb0369
     -(CH₂)nNR¹¹SO₂R¹⁰;
    Figure imgb0370
     ist,
    R⁹   
    Figure imgb0371
     ist,
    R¹⁰   Alkyl mit 1 bis 6 Kohlenstoffatomen oder Perfluoralkyl mit 1 bis 6 Kohlenstoffatomen, 1-Adamantyl, 1-Naphthyl, 1-(1-Naphthyl)ethyl oder (CH₂)pC₆H₅ ist,
    R¹¹   H, Alkyl mit 1 bis 6 Kohlenstoffatomen, Cycloalkyl mit 3 bis 6 Kohlenstoffatomen, Phenyl oder Benzyl ist,
    R¹   H, Methyl oder Benzyl ist,
    R¹³   -CO₂H, -CO₂R⁹, -CH₂CO₂H, -CH₂CO₂R⁹ oder
    Figure imgb0372
    Figure imgb0373
     -SO₃H;
    Figure imgb0374
     -PO₃H₂; -C(CF₃)₂OH; -NHSO₂CH₃; -NHSO₂CF₃; -NHCOCF₃; -CONHOR¹; -SO₂NH₂;
    Figure imgb0375
    Figure imgb0376
     - CONHNHSO₂CF₃ ;
    Figure imgb0377
     ist,
    R¹⁴   H, Alkyl oder Perfluoralkyl mit 1 bis 8 Kohlenstoffatomen, Cycloalkyl mit 3 bis 6 Kohlenstoffatomen, Phenyl oder Benzyl ist,
    R¹⁵   H, Alkyl mit 1 bis 6 Kohlenstoffatomen, Cycloalkyl mit 3 bis 6 Kohlenstoffatomen, Phenyl, Benzyl, Acyl mit 1 bis 4 Kohlenstoffatomen, Phenacyl ist,
    R¹⁶   H, Alkyl mit 1 bis 6 Kohlenstoffatomen, Cycloalkyl mit 3 bis 6 Kohlenstoffatomen, (CH₂)pC₆H₅, OR¹⁷ oder NR¹⁸R¹⁹ ist,
    R¹⁷   H, Alkyl mit 1 bis 6 Kohlenstoffatomen, Cycloalkyl mit 3 bis 6 Kohlenstoffatomen, Phenyl oder Benzyl ist,
    R¹⁸ und R¹⁹   unabhängig H, Alkyl mit 1 bis 4 Kohlenstoffatomen, Phenyl, Benzyl, α-Methylbenzyl sind oder mit dem Stickstoffatom zusammengenommen einen Ring der Formel
    Figure imgb0378
     bilden,
    Q   NR⁰, O oder CH₂ ist,
    R⁰   H, Alkyl mit 1-4 Kohlenstoffatomen oder Phenyl ist,
    R¹   Alkyl mit 1 bis 6 Kohlenstoffatomen, -NRR³ oder
    Figure imgb0379
     ist,
    R und R³   unabhängig H, Alkyl mit 1 bis 6 Kohlenstoffatomen, Benzyl oder zusammengenommen (CH₂)u sind, worin u 3-6 ist,
    R⁴   H, CH₃ oder -C₆H₅ ist,
    R⁵   NR⁷R⁸, OR⁸, NHCONH₂, NHCSNH₂,
    Figure imgb0380
     ist,
    R⁶   Wasserstoff, Alkyl mit 1 bis 6 Kohlenstoffatomen, Benzyl oder Allyl ist,
    R⁷ und R⁸   unabhängig Wasserstoff, Alkyl mit 1 bis 5 Kohlenstoffatomen oder Phenyl sind,
    R⁹ und R³⁰   unabhängig Alkyl mit 1-4 Kohlenstoffatomen oder zusammengenommen -(CH₂)q- sind,
    R³¹   H, Alkyl mit 1 bis 4 Kohlenstoffatomen, -CH₂CH=CH₂ oder -CH₂C₆H₄R³ ist,
    R³   H, NO₂, NH₂, OH oder OCH₃ ist,
    X   eine Kohlenstoff-Kohlenstoff-Einfachbindung, -CO-, -CH₂-, -O-, -S-, -NH-,
    Figure imgb0381
     -OCH₂-, -CH₂O-, -SCH₂-, -CH₂S-, -NHC(R⁷)(R⁸)-, -NR³SO₂-, -SO₂NR³-, -C(R⁷)(R⁸)NH-, -CH=CH-, -CF=CF-, -CH=CF-, -CF=CH-, -CH₂CH₂-, -CF₂CF₂-,
    Figure imgb0382
    Figure imgb0383
     ist,
    Y O oder S ist,
    Z O, NR¹¹ oder S ist,
    m 1 bis 5 ist,
    n 1 bis 10 ist,
    p 0 bis 3 ist,
    q 2 bis 3 ist,
    r 0 bis 2 ist,
    s 0 bis 5 ist,
    t 0 oder 1 ist,
    oder eines pharmazeutisch annehmbaren Salzes derselben, vorausgesetzt, daß
    (1) sich die Gruppe R¹ nicht in ortho-Stellung befindet,
    (2) wenn R¹
    Figure imgb0384
     ist, X eine Einfachbindung ist und R¹³ CO₂H oder
    Figure imgb0385
     ist, R¹³ sich dann in ortho- oder meta- Stellung befinden muß, oder wenn R¹ und X wie vorstehend sind und R¹³ NHSO₂CF₃ oder NHSO₂CH₃ ist, R¹³ ortho sein muß,
    (3) wenn R¹
    Figure imgb0386
     ist und X etwas anderes als eine Einfachbindung ist, R¹³ dann ortho sein muß, außer wenn X = NR³CO und R¹³ NHSO₂CF₃ oder NHSO₂CH₃ ist, R¹³ dann ortho oder meta sein muß,
    (4) wenn R¹ 4-CO₂H oder ein Salz davon ist, R⁶ nicht S-Alkyl sein kann,
    (5) wenn R¹ 4-CO₂H oder ein Salz davon ist, der Substituent in der 4-Stellung des Imidazols nicht CH₂OH, CH₂OCOCH₃ oder CH₂CO₂H sein kann,
    (6) wenn R¹
    Figure imgb0387
     ist, R⁶ nicht Methoxybenzyl ist,
    (7) die Gruppe R⁶ nicht
    Figure imgb0388
     oder CH₂OH ist, wobei das Verfahren
    A) zur Herstellung einer Verbindung, worin r 1 ist, das Zusammenbringen eines Imidazolderivats der Formel 1 mit einem Benzylderivat der Formel 2 in einem Lösungsmittel in Anwesenheit einer Base über 1 bis 10 Stunden bei einer Temperatur im Bereich von 20°C bis zur Rückflußtemperatur des Lösungsmittels unter Bilden eines Benzylimidazols der Formel 3:
    Figure imgb0389
     worin R¹, R, R³, R⁶, R⁷ und R⁸ jeweils unter den Reaktionsbedingungen stabil sind und eine in Anspruch 1 definierte Gruppe oder ein Zwischenprodukt oder eine geschützte Form davon sind, welche in eine derartige Gruppe umgewandelt werden kann und worin X¹ Halogen, p-Toluolsulfonyloxy oder Methylsulfonyloxy ist, und danach nötigenfalls das Umwandeln des Zwischenprodukts oder der geschützten Form der vorstehend definierten Gruppen R in Gruppen R umfaßt,
    B) zur Herstellung einer Verbindung, worin r 0 ist, das Zusammenbringen eines Imidazolderivats der Formel 1 oder seines Metallsalzes mit 4-Fluor-1-nitrobenzol in einem Lösungsmittel in Anwesenheit einer Base, falls das freie Imidazol verwendet wird, während 1-10 Tagen bei einer Temperatur von 25-150°C unter Bilden eines N-Phenylimidazols,
    C) zur Herstellung einer Verbindung, worin R⁷ = vorstehend definiertes substituiertes oder unsubstituiertes Biphenylyl, Phenoxyphenyl oder Heteroaryl, das Kuppeln des Halogenimidazols 237 mit einem Arylmetallderivat ArM, worin M = ZnBr, Me₃Sn oder B(OH)₂, in Anwesenheit eines Übergangsmetallkatalysators wie etwa Palladium, Platin, Nickel oder Zirkonium unter Bilden eines Arylimidazols 238:
    Figure imgb0390
     worin R¹, R, R³, R⁶, R⁸ und r die vorstehend angegebenen Bedeutungen haben, X Br oder I ist, M ZnBr, Me₃Sn, B(OH)₂ ist und Ar für R⁷ vorstehend definiertes substituiertes oder unsubstituiertes Biphenylyl, Phenoxyphenylmethyl oder Heteroaryl ist,
    D) zur Herstellung einer Verbindung, worin R⁷ = vorstehend definiertes substituiertes oder unsubstituiertes Biphenylylmethyl, Phenoxyphenylmethyl oder Heteroarylmethyl, das Kuppeln eines Halogenimidazols 237 mit einem Arylmethylmetallderivat ArCH₂M' in Anwesenheit eines Übergangsmetallkatalysators unter Bilden eines Arylmethylimidazols 240:
    Figure imgb0391
     worin R¹, R, R³, R⁶, R⁸ und r die vorstehend angegebenen Bedeutungen haben, X Br oder I ist, M' ZnBr ist und Ar für R⁷ vorstehend definiertes substituiertes oder unsubstituiertes Heteroaryl, Biphenylmethyl, Phenoxyphenylmethyl ist,
    E) zur Herstellung einer Verbindung, worin R⁷ = Vinyl, Alkinyl, substituiertes Alkenyl oder substituiertes Alkinyl, das Kuppeln eines Halogenimidazols 237 mit einem 1-Alkenylmetall- oder einem 1-Alkinylmetallderivat (AM) oder einem 1-Alken oder einem 1-Alkin (AH) in Anwesenheit eines Übergangsmetallkatalysators unter Bilden eines 1-Alkenyl- oder 1-Alkinylimidazols 241:
    Figure imgb0392
     worin R¹, R, R³, R⁶, R⁸ und r die vorstehend angegebenen Bedeutungen haben, X Br oder I ist, M ein Metall ist, A Vinyl, CH=CH(CH₂)xAr, C≡C(CH₂)yCH₃, C≡C(CH₂)zPh' oder C≡C(CH₂)xAr ist, Ph' Phenyl oder substituiertes Phenyl ist und Ar vorstehend definiertes substituiertes oder unsubstituiertes Biphenylyl, Phenoxyphenyl oder Heteroaryl ist, x = 0-8, y = 0-7 und z = 0-4,
    F) zur Herstellung einer Verbindungen, worin R⁷ = Vinyl oder substituiertes Alkenyl, das Umsetzen eines Imidazolaldehyds 253 mit Methylentriphenylphosphoran oder einem substituierten Methylentriphenylphosphoran unter Bilden eines Vinylimidazols oder eines substituierten Alkenylimidazols 254:
    Figure imgb0393
     worin n=O-5 worin R¹, R, R³, R⁶, R⁸ und r die vorstehend angegebenen Bedeutungen haben, Ar vorstehend definiertes substituiertes oder unsubstituiertes Biphenylyl, Phenoxyphenyl oder Heteroaryl ist und u + v = 0 bis 8,
    G) zur Herstellung einer Verbindung der Formel I, worin R⁷-S(O)r-Heteroaryl, -S-(O)r-Biphenylyl, -S(O)r-Phenoxyphenyl, -S-Tetrazol, -S(O)rR¹⁷, -NR¹⁸R¹⁹, -NR¹⁸-Heteroaryl, -NR¹⁸-Phenyl, -NR¹⁸-Biphenylyl, -NR¹⁸-Phenoxyphenyl, -N-Phthalimido, -NH-SO₂-Phenoxyphenyl, -NH-SO₂-Heteroaryl, -NH-SO₂-Biphenylyl, -NH-SO₂-R¹⁷ und -S-(C=O)R¹⁷, N-Imidazolyl, N-1,2,3-Triazolyl und N-1,2,4-Triazolyl ist, wobei Heteroaryl wie vorstehend definiert ist, das Umsetzen mit einer elektronenziehenden Gruppe E substituierter imidazolhaltiger Verbindungen 255 mit Nukleophilen in einem geeigneten Lösungsmittel bei Raumtemperatur bis zur Rückflußtemperatur des Lösungsmittels umfaßt, was eine aromatische Substitutionsreaktion zur Folge hat, wodurch die Abgangsgruppe X durch ein Nukleophil Nu wie etwa Schwefel oder Stickstoff unter Erzeugen von Verbindungen der Struktur 256 substituiert wird:
    Figure imgb0394
  2. Verfahren von Anspruch 1, wobei in A Verbindung 1 und 2 in Anwesenheit einer Base, die aus der Gruppe ausgewählt ist, die aus einem Metallhydrid (MH), einem Metallalkoxid (MOR), Natriumcarbonat, Kaliumcarbonat, Triethylamin und Pyridin besteht, in einem dipolaren aprotischen Lösungsmittel zusammengebracht werden oder, wenn die Base MOR ist, das Lösungsmittel ein Alkohol, ROH, sein kann, worin M Lithium, Natrium oder Kalium ist und R Methyl, Ethyl oder t-Butyl ist.
  3. Verfahren von Anspruch 1, wobei in A ein Zweiphasen-Lösungsmittelsystem, eines eine organische Phase wie etwa Methylenchlorid und das andere eine wäßrige Phase, in Anwesenheit eines Phasentransferkatalysators wie etwa Tricaprylmethylammoniumchlorid verwendet wird.
  4. Verfahren von Anspruch 2, wobei R¹
    Figure imgb0395
     ist,
    X   eine Kohlenstoff-Kohlenstoff-Einfachbindung, -CO-, -O-, -S- oder -NH- ist,
    R und R³   jeweils unabhängig H, Cl, Br, I, CO₂R¹⁴, F, NO₂, Alkyl mit 1 bis 4 Kohlenstoffatomen, Alkoxy mit 1 bis 4 Kohlenstoffatomen, Phenyl oder Furyl sind,
    R⁶ und R⁷   wie in Anspruch 1 definiert sind,
    R⁸   -(CH₂)nOR¹¹, -(CH₂)nSR¹⁵ oder -(CH₂)nCN ist,
    R¹¹   wie in Anspruch 1 ist,
    R¹³   CO₂R¹⁴, CN, NO₂, Trialkylzinntetrazol oder Trityltetrazol ist und
    R¹⁴ und R¹⁵   wie in Anspruch 1 definiert sind.
  5. Verfahren von Anspruch 4, wobei R¹³ -CO₂R¹⁴ ist und das Produkt der Formel 3 1-24 Stunden mit einer Alkalie in einem wäßrig-alkoholischen Lösungsmittel oder mit CF₃CO₂H bei einer Temperatur im Bereich von 20°C bis zur Rückflußtemperatur des Lösungsmittels zusammengebracht wird, gefolgt von der Einstellung des pH des Gemisches auf einen Wert im Bereich von 3 bis 7 unter Überführen des Produkts in das entsprechende Produkt, worin R¹³ -CO₂H ist.
  6. Verfahren von Anspruch 5, wobei wenigstens eines von R, R³ oder R¹³ in Formel 1 -CO₂R¹⁴ ist und in -CO₂H überführt wird.
  7. Verfahren von Anspruch 5, wobei R¹⁴ t-Butyl ist und die Reaktion in CF₃CO₂H ausgeführt wird.
  8. Verfahren von Anspruch 4, wobei R¹³ -CN ist und das Produkt der Formel 3 mit (i) einer starken Säure 2-96 Stunden bei der Rückflußtemperatur des Lösungsmittels oder (ii) einem starken Alkali in einem Alkohollösungsmittel 2-96 Stunden bei einer Temperatur im Bereich von 20°C und der Rückflußtemperatur des Lösungsmittels, gefolgt von der Einstellung des pH auf 3-7, oder (iii) Schwefelsäure gefolgt von Säure oder Alkali unter Überführen des Produkts in die entsprechende Verbindung, worin R¹³ -CO₂H ist, zusammengebracht wird.
  9. Verfahren von Anspruch 8, wobei wenigstens eines von R, R³ oder R¹³ -CO₂R¹⁴ ist, und in -CO₂H überführt wird.
  10. Verfahren von Anspruch 8, wobei R⁸ -(CH₂)nCN ist und in -(CH₂)nCO₂H überführt wird oder -(CH₂)nOR¹¹ ist und in (CH₂)nOH überführt wird, wenn R¹³ in -CO₂H überführt wird.
  11. Verfahren von Anspruch 4, wobei R¹³ -CN ist, und das Produkt der Formel 3 mit einem Gemisch äquimolarer Mengen Natriumazid und Ammoniumchlorid in einem polaren aprotischen Lösungsmittel bei einer Temperatur im Bereich von 30°C bis zur Rückflußtemperatur des Lösungsmittels 1 Stunde bis 10 Tage unter Überführen des Produkts in die entsprechende Verbindung, worin R¹³ 5-Tetrazolyl ist, zusammengebracht wird.
  12. Verfahren von Anspruch 11, wobei R⁸ -(CH₂)mCN ist und in -(CH₂)m-Tetrazolyl überführt wird, wenn R¹³ in 5-Tetrazolyl überführt wird.
  13. Verfahren von Anspruch 4, wobei R¹³ -CN ist, und das Produkt der Formel 3 mit Trialkylzinnazid oder Triarylzinnazid umgesetzt wird, gefolgt von saurer oder basischer Hydrolyse unter Überführen des Produkts in die entsprechende Verbindung, worin R¹³ 5-Tetrazolyl ist.
  14. Verfahren von Anspruch 4, wobei R¹³ -CN ist und das Produkt der Formel 3 mit Trialkylzinnazid oder Triarylzinnazid unter Herstellen einer Verbindung der Formel 3 umgesetzt wird, worin R¹³ Trialkyl- oder Triarylstannyltetrazol-5-yl ist, letztere Verbindung mit Triphenylmethylchlorid unter Erzeugen einer Verbindung der Formel 3, worin R¹³ Triphenylmethyltetrazol-5-yl ist, umgesetzt wird und letztere Verbindung unter Erzeugen einer Verbindung der Formel 3, worin R¹³ 5-Tetrazolyl ist, hydrolysiert wird.
  15. Verfahren von Anspruch 3, worin R⁸ -(CH₂)nCN ist und in -(CH₂)m-Tetrazolyl überführt wird, wenn R¹³ in 5-Tetrazolyl überführt wird.
  16. Verfahren von Anspruch 4, wobei R¹³ -NO₂ ist und das Produkt der Formel 3 mit einem Reduktionsmittel unter Bilden eines zweiten Zwischenprodukts der Formel 3, in der R¹³ NH₂ ist, zusammengebracht wird und letztere mit einem Sulfonsäureanhydrid (CH₃So₂)₂O oder (CF₃SO₂)₂O oder -chlorid CH₃SO₂Cl oder CF₃SO₂Cl in einem Lösungsmittel unter Herstellen einer Verbindung zusammengebracht wird, in welcher R¹³ -NHSO₂CH₃ oder -NHSO₂CF₃ ist.
  17. Verfahren von Anspruch 16, wobei wenigstens eines von R, R³ oder R¹³ -NO₂ ist und in -NHSO₂CH₃ oder-NHSO₂CF₃ überführt wird.
  18. Verfahren von Anspruch 5 oder 8, wobei die Verbindung der Formel 3 mit R¹³ = CO₂H unter Liefern einer Verbindung, in der R¹³ CONHOR¹ ist, entweder
    (a) mit etwa 1-4 Äquivalenten Thionylchlorid in überschüssigem Thionylchlorid oder einem weiteren Lösungsmittel bei einer Temperatur im Bereich von 20°C bis zur Rückflußtemperatur des Lösungsmittels über einen Zeitraum von 5 Minuten bis 2 Stunden unter Bilden eines Zwischenproduktes der Formel 3, worin R¹³ COCl ist, zusammengebracht wird und letzteres 2-18 Stunden bei einer Temperatur im Bereich von 25-80°C mit 2-10 Äquivalenten eines Hydroxylaminderivates H₂NOR¹ in überschüssigem Hydroxylaminderivat H₂NOR¹ oder einem anderen Lösungsmittel zusammengebracht wird, oder
    (b) mit dem Hydroxylaminderivat H₂NOR¹, Dicyclohexylcarbodiimid und 1-Hydroxybenzotriazol in einem Lösungsmittel bei einer Temperatur im Bereich von 0-30°C 1-24 Stunden zusammengebracht wird.
  19. Verfahren von Anspruch 1, wobei in A) R¹
    Figure imgb0396
     ist,
    X   eine Kohlenstoff-Kohlenstoff-Einfachbindung, -CO-, -O-, -S- oder -NH- ist,
    R, R³, R⁶ und R⁷   wie in Anspruch 1 definiert sind und
    R⁸   (CH₂)nOR¹¹, (CH₂)nOCOR¹⁴, (CH₂)nCH(OH)R¹⁶, (CH₂)nCOR¹⁶(CH₂)nCl, (CH₂)nCN, CHO ist.
  20. Verfahren von Anspruch 19, wobei R⁸ (CH₂)nOH ist und das Produkt der Formel 3 mit einem Alkohol R¹¹OH in wasserfreiem Zustand in Anwesenheit einer starken Säure oder einer Lewissäure zusammengebracht wird, gefolgt von der Verseifung irgendwelcher Gruppen CO₂R¹⁴, die im Zwischenprodukt gleichzeitig gebildet werden oder zugegen sind, unter Bilden der entsprechenden Verbindung der Formel 3, worin R⁸ (CH₂)nOR¹¹ ist und R¹¹ nicht H ist.
  21. Verfahren von Anspruch 19, wobei R⁸ (CH₂)nOR¹¹ ist und R¹¹ nicht H ist und das Produkt der Formel 3 mit einem wäßrigen sauren Medium bei einer Temperatur im Bereich von 25°C und der Rückflußtemperatur des Lösungsmittels über einen Zeitraum von 0,5-24 Stunden unter Bilden der entsprechenden Verbindung der Formel 3, worin R⁸ (CH₂)nOH ist, zusammengebracht wird.
  22. Verfahren von Anspruch 19, wobei R⁸ (CH₂)nOH ist und das Produkt der Formel 3 mit
    (a) einem Carbonsäureanhydrid (R¹⁴CO)₂O oder -chlorid R¹⁴COCl 0,5-24 Stunden in einem Lösungsmittel in Anwesenheit einer Base bei einer Temperatur im Bereich von 0°C und der Rückflußtemperatur des Lösungsmittels oder
    (b) eine Carbonsäure R¹⁴CO₂H unter wasserfreien Bedingungen in Anwesenheit einer starken Säure oder Lewissäure 0,5 bis 24 Stunden bei 0°-100°C unter Bilden der entsprechenden Verbindung, in der R⁸ (CH₂)nOCOR¹⁴ ist, zusammengebracht wird.
  23. Verfahren von Anspruch 19, wobei R⁸ (CH₂)nOCOR¹⁴ ist und das Produkt der Formel 3 mit wäßriger Säure oder Alkali unter Bilden der entsprechenden Verbindung, worin R⁸ (CH₂)nOH ist, zusammengebracht wird.
  24. Verfahren von Anspruch 19, wobei R⁸ (CH₂)nOH ist und das Produkt der Formel 3 mit einem Oxidationsmittel 1-200 Stunden bei einer Temperatur von 25-45°C unter Herstellen einer entsprechenden Verbindung der Formel 3 zusammengebracht wird, in welcher R⁸ (CH₂)n-1COR¹⁶ ist und R¹⁶ H ist.
  25. Verfahren von Anspruch 19, wobei R⁸ (CH₂)nCOR¹⁶ ist und R¹⁶ H ist und das Produkt der Formel 3 mit einer metallorganischen Verbindung R¹⁶P, in der P MgBr oder Li ist, 0,5-24 Stunden bei einer Temperatur im Bereich von -78°C bis 100°C unter Bilden einer Verbindung der Formel 3 zusammengebracht wird, in welcher R⁸ (CH₂)nCH(OH)R¹⁶ ist und R¹⁶ nicht H ist.
  26. Verfahren von Anspruch 19, wobei R⁸ (CH₂)nCH(OH)R¹⁶ ist und R¹⁶ nicht H ist und das Produkt der Formel 3 mit einem Oxidationsmittel in einem Lösungsmittel unter Bilden einer entsprechenden Verbindung der Formel 3 zusammengebracht wird, in welcher R⁸ (CH₂)nCOR¹⁶ ist und R¹⁶ nicht H ist.
  27. Verfahren von Anspruch 19, wobei R⁸ (CH₂)nCOR¹⁶ ist und R¹⁶ H ist und die Verbindung der Formel 3 mit einem Oxidationsmittel in einem Lösungsmittel unter Bilden einer entsprechenden Verbindung der Formel 3 zusammengebracht wird, in welcher R⁸ (CH₂)nCOR¹⁶ ist und R¹⁶ OH ist.
  28. Verfahren von Anspruch 19, wobei R⁸ (CH₂)nCOR¹⁶ ist und R¹⁶ OH ist und die Verbindung der Formel 3 mit Thionylchlorid im Überschuß oder einem weiteren Lösungsmittel bei einer Temperatur im Bereich von 0°C bis zur Rückflußtemperatur des Lösungsmittels 5 Minuten bis 24 Stunden unter Bilden einer entsprechenden Verbindung der Formel 3, in der R⁸ (CH₂)nCOCl ist, zusammengebracht wird, gefolgt vom Zusammenbringen der letzteren mit einem Amin NHR¹⁸R¹⁹ im Überschuß oder in einem Lösungsmittel 5 Minuten bis 24 Stunden bei Temperaturen im Bereich von 0°C und Rückflußtemperatur des Lösungsmittels unter Bilden. einer entsprechenden Verbindung der Formel 3, in der R⁸ (CH₂)nCONR¹⁸R¹⁹ ist.
  29. Verfahren von Anspruch 19, wobei R⁸ (CH₂)nOR¹¹ ist und R¹¹ H ist und das Produkt der Formel 3 mit Thionylchlorid im Überschuß oder in einem Lösungsmittel bei einer Temperatur im Bereich von 20°C bis zur Rückflußtemperatur des Lösungsmittels 0,5-24 Stunden unter Bilden einer Zwischenproduktverbindung der Formel 3 zusammengebracht wird, in der R⁸ (CH₂)nCl ist.
  30. Verfahren von Anspruch 29, wobei die Verbindung der Formel 3, in der R⁸ (CH₂)nCl ist, mit dem Natrium- oder Kaliumsalz eines Mercaptans R¹⁵SH 1-24 Stunden in einem Lösungsmittel bei einer Temperatur von 25-100°C unter Bilden einer Verbindung der Formel zusammengebracht wird, in welcher R⁸ (CH₂)nSR¹⁵ ist.
  31. Verfahren von Anspruch 19, wobei die Verbindung der Formel 3, in der R⁸ (CH₂)nCl ist, mit einem Alkalimetallcyanid 1-24 Stunden in einem Lösungsmittel bei einer Temperatur im Bereich von 20-100°C unter Bilden einer Verbindung der Formel 3 zusammengebracht wird, in welcher R⁸ (CH₂)nCN ist und die letztere Verbindung zu der entsprechenden Verbindung der Formel 3 hydrolysiert wird, in der R⁸ (CH₂)nCOR¹⁶ ist und R¹⁶ OH ist.
  32. Verfahren von Anspruch 19, wobei die Verbindung der Formel 3, in der R⁸(CH₂)n_₁Cl ist, mit dem Natrium- oder Kaliumsalz eines Malonsäuredialkylesters 0,5-24 Stunden in einem Lösungsmittel bei einer Temperatur im Bereich von 20-100°C unter Bilden einer Verbindung der Formel 3 zusammengebracht wird, in welcher R⁸ (CH₂)n-1CH(CO₂Alkyl)₂ ist, gefolgt von der Verseifung der letzteren mit wäßrigem Alkali bei einer Temperatur im Bereich von 25 °C bis zur Rückflußtemperatur des Lösungsmittels, gefolgt vom Ansäuern mit Mineralsäure unter Bilden einer Verbindung der Formel 3, in der R⁸ (CH₂)n-1CH(CO₂H)₂ ist, gefolgt vom Erhitzen der letzteren auf 120°C oder in verdünnter Mineralsäure bei Rückflußtemperatur unter Bilden eines Produkts der Formel 3, in der R⁸ (CH₂)nCOR¹⁶ ist und R¹⁶ OH ist.
  33. Verfahren von Anspruch 19, wobei R⁸ -CHO ist und die Verbindung der Formel 3 mit einem Methylenphosphoran (C₆H₅)₃P=CH(CH₂)nCHR¹⁴OR¹⁵ oder (C₆H₅)₃P=CH(CH₂)sCOR¹⁶ 1-24 Stunden in einem Lösungsmittel bei einer Temperatur im Bereich von 25°C bis zur Rückflußtemperatur des Lösungsmittels unter Bilden einer Verbindung der Formel 3 zusammengebracht wird, in welcher R⁸ -CH=CH(CH₂)sCHR¹⁴OR¹⁵ oder -CH=CH(CH₂)sCOR¹⁶ ist, außer wenn R¹⁵ H ist und R¹⁶ OH ist, und gegebenenfalls anschließend 0,5-24 Stunden Zusammenbringen der Verbindung der Formel 3, in der R⁸ -CH=CH(CH₂)sCOR¹⁶ ist, mit einem Reduktionsmittel in einem Lösungsmittel bei einer Temperatur im Bereich von 0-25°C unter Bilden eines Produkts der Formel 3, in der R⁸ -CH=CH(CH₂)sCHR¹⁴OH ist.
  34. Verfahren von Anspruch 19, wobei R⁸ (CH₂)nOH ist und die Verbindung der Formel 3 mit einem Isocyanat der Formel R¹⁰NCO in einem Lösungsmittel bei einer Temperatur im Bereich von 25°C bis zur Rückflußtemperatur des Lösungsmittels über einen Zeitraum von 5 Minuten bis 24 Stunden unter Bilden einer Verbindung der Formel 3 zusammengebracht wird, in welcher R⁸ (CH₂)nOCONHR¹⁰ ist.
  35. Verfahren von Anspruch 19, wobei die Verbindung in der R⁸ (CH₂)nCl ist, mit einem Amin R¹¹NH₂ in überschüssigem Amin oder einem weiteren Lösungsmittel über einen Zeitraum von 1-24 Stunden bei einer Temperatur im Bereich von 0°C bis zur Rückflußtemperatur des Lösungsmittels unter Bilden eines Zwischenprodukts der Formel 3 zusammengebracht wird, in welcher R⁸ (CH₂)nNHR¹¹ ist.
  36. Verfahren von Anspruch 19, wobei R⁸ (CH₂)nCl ist und die Verbindung der Formel 3 mit einem Alkalimetallazid in einem aprotischen Lösungsmittel 1-24 Stunden bei einer Temperatur im Bereich von 25-80°C unter Bilden einer Verbindung der Formel 3 zusammengebracht wird, in welcher R⁸ (CH₂)nN₃ ist und die letztere mit einem Reduktionsmittel unter Bilden eines Zwischenprodukts der Formel 3 zusammengebracht wird, in welcher R⁸ (CH₂)nNH₂ ist.
  37. Verfahren von Anspruch 35 oder 36, wobei R⁸ (CH₂)nNHR¹¹ oder (CH₂)nNH₂ ist und die Verbindung der Formel 3 mit einem Chlorameisensäureester der Formel R¹⁰OCOCl oder einem Sulfonylderivat der Formel R¹⁰SO₂Cl oder (R¹⁰SO₂)₂O in einem Lösungsmittel in Anwesenheit einer Base 5 Minuten bis 24 Stunden bei einer Temperatur im Bereich von 0°C bis zur Rückflußtemperatur des Lösungsmittels unter Bilden einer Verbindung der Formel 3 zusammengebracht wird, in welcher R⁸ -(CH₂)nNR¹¹CO₂R¹⁰ oder -(CH₂)nNR¹¹SO₂R¹⁰ ist.
  38. Verfahren von Anspruch 35 oder 36, wobei die Verbindung der Formel 3 mit R⁸ gleich -(CH2)nNHR¹¹ oder (CH₂)nNH₂ mit einem Isocyanat oder Isothiocyanat R¹⁰NCY 5 Minuten bis 24 Stunden bei einer Temperatur im Bereich von 25°C bis zur Rückflußtemperatur des Lösungsmittels unter Bilden einer Verbindung der Formel 3 zusammengebracht wird, in welcher R⁸ -(CH₂)nNR¹¹CYNHR¹⁰ ist.
  39. Verfahren von Anspruch 1, wobei R¹ in A) und B) NO₂ ist und R, R³, R⁶, R⁷ und R⁸ wie in Anspruch 24 definiert sind, wobei eine Verbindung, in welcher R¹ NO₂ ist, mittels Eisen und Essigsäure, Zinn(II)-chlorid oder Wasserstoff und Palladium zu einer Verbindung reduziert wird, worin R¹ NH₂ ist und letztere mit einem entsprechenden Säureanhydrid wie etwa Phthalanhydrid oder einem substituierten Phthalanhydrid in einem Lösungsmittel oder mit einem entsprechenden Säurechlorid wie etwa einem substituierten Anthranilsäurechlorid in Anwesenheit wäßrigen Alkalis oder einer Base oder mit einer entsprechend substituierten Phthal- oder Anthranilsäure in Anwesenheit von Dicyclohexylcarbodiimid unter Herstellen einer Verbindung umgesetzt wird, in welcher R¹
    Figure imgb0397
     ist, und X NHCO ist.
  40. Verfahren von Anspruch 1, wobei.in A) R¹ OCH₂C₆H₅ ist, R und R³ H sind und R⁶, R⁷ und R⁸ wie in Anspruch 1 definiert sind und die sich daraus ergebende Verbindung der Formel 3 mit R¹ gleich OCH₂C₆H₅ über einen Zeitraum von 0,2-1 Stunde mit Trifluoressigsäure bei Rückflußtemperatur oder mit Wasserstoff und Palladium unter Bilden der entsprechenden Verbindung der Formel 3 umgesetzt wird, in welcher R¹ OH ist und letztere mit einer Base bei 25°C und einem geeigneten Benzylhalogenid der Formel
    Figure imgb0398
     unter Herstellen der entsprechenden Verbindung der Formel 3 zusammengebracht wird, worin R¹
    Figure imgb0399
     ist,
    und X -OCH₂- ist.
  41. Verfahren von Anspruch 1, wobei R⁸ in A) -CHO ist, wobei das Benzylderivat der Formel 2 an dem Imidazolderivat der Formel 1 vorzugsweise an das dem Kohlenstoffatom des Imidazolrings, an das R⁸ gebunden ist, benachbarte Stickstoffatom gebunden ist.
  42. Verfahren von Anspruch 19, wobei R⁸ CHO ist und X eine Kohlenstoff-Kohlenstoff-Einfachbindung ist und das Produkt der Formel 3 mit einem metallorganischen Reagenz wie etwa R¹¹MgBr oder R¹¹Li in Anwesenheit eines wasserfreien Lösungsmittels ohne Hydroxylgruppen wie etwa Ether, THF oder Dimethoxyethan bei -78 bis 25°C, gefolgt von wäßriger Aufarbeitung, gefolgt von der sauren Hydrolyse irgendwelcher Gruppen CO₂R¹⁴, worin R¹⁴ t-Butyl ist, oder der Hydrolyse irgendwelcher tritylgeschützter Tetrazolgruppen unter Bilden der entsprechenden Verbindung der Formel 3, worin R⁸
    Figure imgb0400
     ist, worin R¹¹ ≠ H.
  43. Verfahren gemäß einem der Ansprüche 1-42, wobei die hergestellte Verbindung die Formel
    Figure imgb0401
     worin
    R¹   - CO₂H ; -NHSO₂CF₃ ;
    Figure imgb0402
     oder
    Figure imgb0403
     ist,
    R⁶   Alkyl mit 3 bis 10 Kohlenstoffatomen, Alkenyl mit 3 bis 10 Kohlenstoffatomen, Alkinyl mit 3 bis 10 Kohlenstoffatomen, Cycloalkyl mit 3 bis 8 Kohlenstoffatomen, Benzyl ist, das am Phenylring mit bis zu zwei Gruppen substituiert ist, die aus Alkoxy mit 1 bis 4 Kohlenstoffatomen, Halogen, Alkyl mit 1 bis 4 Kohlenstoffatomen und Nitro ausgewählt sind,
    R⁸   -(CH₂)m-Tetrazolyl, -(CH₂)nOR¹¹;
    Figure imgb0404
    Figure imgb0405
    Figure imgb0406
     -(CH₂)nNHSO₂R¹⁰ ; oder
    Figure imgb0407
     ist,
    R¹³   -CO₂H, -CO₂R⁹, NHSO₂CF₃, SO₃H oder
    Figure imgb0408
     ist,
    R¹⁶   H, Alkyl mit 1 bis 5 Kohlenstoffatomen, OR¹⁷ oder NR¹⁸R¹⁹ ist,
    X   eine Kohlenstoff-Kohlenstoff-Einfachbindung, -CO-,
    Figure imgb0409
     -CH₂CH₂- ,
    Figure imgb0410
     -OCH₂- , -CH₂O-, -O-, -SCH₂- , -CH₂S - , -NHCH₂- , -CH₂NH- oder -CH=CH- ist,
    oder eines pharmazeutisch annehmbaren Salzes derselben besitzt.
  44. Verfahren von Anspruch 43, wobei
    R   H, Alkyl mit 1 bis 4 Kohlenstoffatomen, Halogen oder Alkoxy mit 1 bis 4 Kohlenstoffatomen ist,
    R⁶   Alkyl, Alkenyl oder Alkinyl mit 3 bis 7 Kohlenstoffatomen ist,
    R⁷   Heteroaryl ist, das aus 2- und 3-Thienyl, 2- und 3-Furyl, 2-, 3- und 4-Pyridyl oder p-Biphenylyl
    Figure imgb0411
     ausgewählt ist,
    R⁸   -(CH₂)mOR¹¹ ;
    Figure imgb0412
    Figure imgb0413
     -(CH₂)mNHSO₂R¹⁰ oder -COR¹⁶ ist,
    R¹⁰   CF₃, Alkyl mit 1 bis 6 Kohlenstoffatomen oder Phenyl ist,
    R¹¹   H oder Alkyl mit 1 bis 4 Kohlenstoffatomen ist,
    R¹³   CO₂H, CO₂CH₂OCOC(CH₃)₃, NHSO₂CF₃ oder
    Figure imgb0414
     ist,
    R¹⁴   H oder Alkyl mit 1 bis 4 Kohlenstoffatomen ist,
    R¹⁵   H, Alkyl mit 1 bis 4 Kohlenstoffatomen oder Acyl mit 1 bis 4 Kohlenstoffatomen ist,
    R¹⁶   H, Alkyl mit 1 bis 5 Kohlenstoffatomen, OR¹⁷ oder
    Figure imgb0415
     ist,
    m   1 bis 5 ist,
    X = Einfachbindung, -O-, -CO-, -NHCO- oder -OCH₂-, oder ein pharmazeutisch annehmbares Salz davon.
  45. Verfahren von Anspruch 44, wobei R¹
    Figure imgb0416
     ist und X eine Einfachbindung ist oder ein pharmazeutisch geeignetes Salz davon.
  46. Verfahren zur Herstellung einer pharmazeutischen Zusammensetzung, welches das Vermischen eines pharmazeutisch geeigneten Trägers mit einer gemäß einem der Ansprüche 1 bis 45 hergestellten Verbindung umfaßt.
  47. Verfahren von Anspruch 46, wobei die pharmazeutische Zusammensetzung zusätzlich einen diuretischen oder einen nicht-steroidalen, entzündungshemmenden Wirkstoff enthält.
EP90911154A 1989-06-30 1990-06-28 Substituierte imidazole und ihre verwendung als hemmmstoff fur angiotensin ii Expired - Lifetime EP0479903B1 (de)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US37375589A 1989-06-30 1989-06-30
US373755 1989-06-30
US54524090A 1990-06-27 1990-06-27
US54455790A 1990-06-27 1990-06-27
US544557 1990-06-27
US545240 1990-06-27
PCT/US1990/003683 WO1991000277A1 (en) 1989-06-30 1990-06-28 Substituted imidazoles

Publications (2)

Publication Number Publication Date
EP0479903A1 EP0479903A1 (de) 1992-04-15
EP0479903B1 true EP0479903B1 (de) 1996-02-21

Family

ID=27409142

Family Applications (1)

Application Number Title Priority Date Filing Date
EP90911154A Expired - Lifetime EP0479903B1 (de) 1989-06-30 1990-06-28 Substituierte imidazole und ihre verwendung als hemmmstoff fur angiotensin ii

Country Status (15)

Country Link
EP (1) EP0479903B1 (de)
JP (1) JP2550442B2 (de)
KR (1) KR0163595B1 (de)
AT (1) ATE134368T1 (de)
AU (1) AU644802B2 (de)
CA (1) CA2060656A1 (de)
DE (1) DE69025473T2 (de)
DK (1) DK0479903T3 (de)
ES (1) ES2084702T3 (de)
FI (1) FI916129A0 (de)
HU (1) HU217958B (de)
NO (1) NO915113L (de)
RU (1) RU2099330C1 (de)
SG (1) SG52709A1 (de)
WO (1) WO1991000277A1 (de)

Families Citing this family (61)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5210079A (en) * 1988-01-07 1993-05-11 E. I. Du Pont De Nemours And Company Treatment of chronic renal failure with imidazole angiotensin-II receptor antagonists
IL97219A (en) * 1990-02-19 1995-12-08 Ciba Geigy Ag Biphenyl substituted aliphatic amino compounds process for their preparation and pharmaceutical compositions containing them
ATE146076T1 (de) * 1990-06-22 1996-12-15 Du Pont Behandlung des chronischen nierenversagens mit imidazol-angiotensin-ii-rezeptorantagonisten
US5137902A (en) * 1990-07-13 1992-08-11 E. I. Du Pont De Nemours And Company 4-alkylimidazole derivatives and anti-hypertensive use thereof
CA2058198A1 (en) * 1991-01-04 1992-07-05 Adalbert Wagner Azole derivatives, process for their preparation, and their use
AT395853B (de) * 1991-01-31 1993-03-25 Chem Pharm Forsch Gmbh Neue imidazolderivate, verfahren zu ihrer herstellung und ihre verwendung
FR2672892B1 (fr) * 1991-02-20 1994-01-14 Synthelabo Derives de 4-pyrimidinones, leur preparation et leur application en therapeutique.
US5616599A (en) * 1991-02-21 1997-04-01 Sankyo Company, Limited Angiotensin II antagosist 1-biphenylmethylimidazole compounds and their therapeutic use
GB9110636D0 (en) * 1991-05-16 1991-07-03 Glaxo Group Ltd Chemical compounds
US5210211A (en) * 1991-06-21 1993-05-11 Warner-Lambert Company 4-(1h-pyrrol-1-yl) imidazoles with angiotension ii antagonist activity
DE4132633A1 (de) * 1991-10-01 1993-04-08 Bayer Ag Cyclisch substituierte imidazolyl-propensaeurederivate
DE4132631A1 (de) * 1991-10-01 1993-04-08 Bayer Ag Imidazolyl-propensaeurederivate
US5308853A (en) * 1991-12-20 1994-05-03 Warner-Lambert Company Substituted-5-methylidene hydantoins with AT1 receptor antagonist properties
FR2687674B1 (fr) * 1992-02-07 1995-05-19 Roussel Uclaf Nouveaux derives de la pyridone, leur procede de preparation, les nouveaux intermediaires obtenus, leur application a titre de medicaments et les compositions pharmaceutiques les renfermant.
US5219856A (en) * 1992-04-06 1993-06-15 E. I. Du Pont De Nemours And Company Angiotensin-II receptor blocking, heterocycle substituted imidazoles
EP0573218B1 (de) * 1992-06-02 2001-03-07 Sankyo Company Limited 4-Carboxyimidazolderivate als Angiotensin-II-Antagonisten und ihre therapeutische Verwendung
GB9213934D0 (en) * 1992-06-30 1992-08-12 Smithkline Beecham Corp Chemical compounds
US5310929A (en) * 1992-08-06 1994-05-10 E. I. Du Pont De Nemours And Company Prodrugs of imidazole carboxylic acids as angiotensin II receptor antagonists
IT1255802B (it) * 1992-08-07 1995-11-16 Luso Farmaco Inst Derivati imidazolici ad attivita' a ii antagonista
JP3501484B2 (ja) * 1992-12-17 2004-03-02 三共株式会社 ビフェニル誘導体
US5721263A (en) 1993-06-07 1998-02-24 Takeda Chemical Industries, Ltd. Pharmaceutical composition for angiotensin II-mediated diseases
IT1273790B (it) * 1994-02-18 1997-07-10 Guidotti & C Spa Labor Derivati eterociclici diazotati aventi attivita' aii antagonista
MX9604109A (es) * 1994-03-16 1997-09-30 Sankyo Co Agente para disminuir la tension ocular.
US6613789B2 (en) 1994-07-28 2003-09-02 G. D. Searle & Co. Heterocyclo-substituted imidazoles for the treatment of inflammation
US5616601A (en) * 1994-07-28 1997-04-01 Gd Searle & Co 1,2-aryl and heteroaryl substituted imidazolyl compounds for the treatment of inflammation
WO1999044590A1 (en) 1998-03-04 1999-09-10 Takeda Chemical Industries, Ltd. Sustained-release preparation for aii antagonist, production and use thereof
ATE467620T1 (de) 1999-03-26 2010-05-15 Euro Celtique Sa Arylsubstituierte pyrazole, imidazole, oxazole, thiazole und pyrrole, sowie deren verwendung
US7125875B2 (en) 1999-04-15 2006-10-24 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
KR100722344B1 (ko) 1999-04-15 2007-05-29 브리스톨-마이어스스퀴브컴파니 환형 단백질 티로신 키나제 억제제
SE9903028D0 (sv) 1999-08-27 1999-08-27 Astra Ab New use
GB0011089D0 (en) * 2000-05-08 2000-06-28 Black James Foundation Gastrin and cholecystokinin receptor ligands (11)
MXPA03004862A (es) 2000-12-04 2005-02-14 Hoffmann La Roche Derivados de feniletenilo o feniletinilo como antagonistas del receptor de glutamato.
JP4267920B2 (ja) 2001-01-26 2009-05-27 中外製薬株式会社 代謝調節剤として有用なマロニル−ＣｏＡ脱炭酸酵素阻害剤
CN101596191B (zh) 2001-01-26 2011-06-15 中外制药株式会社 用作代谢调节剂的丙二酰基辅酶a脱羧酶抑制剂
US7385063B2 (en) 2001-01-26 2008-06-10 Chugai Seiyaku Kabushiki Kaisha Method for preparing imidazole derivatives
US7709510B2 (en) 2001-02-20 2010-05-04 Chugai Seiyaku Kabushiki Kaisha Azoles as malonyl-CoA decarboxylase inhibitors useful as metabolic modulators
DE60233650D1 (de) 2001-02-20 2009-10-22 Chugai Pharmaceutical Co Ltd Verfahren zur behandlung von stoffwechselerkrankungen mit malonyl-coa-decarboxylase-hemmern
JP2005514455A (ja) 2001-12-21 2005-05-19 ファルマシア・コーポレーション 芳香族チオエーテル肝臓ｘ受容体モジュレータ
MXPA04011690A (es) 2002-05-24 2005-03-31 Pharmacia Corp Moduladores de receptor x de higado de sulfona.
MXPA04011691A (es) 2002-05-24 2005-09-12 Pharmacia Corp Moduladores del receptor x anilino hepaticos.
TWI292318B (en) 2003-03-10 2008-01-11 Hoffmann La Roche Imidazol-4-yl-ethynyl-pyridine derivatives
ATE375810T1 (de) 2003-08-01 2007-11-15 Chugai Pharmaceutical Co Ltd Cyanoamid-verbindungen als nützliche malonyl-coa decarboxylase-hemmer
ES2353306T3 (es) 2003-08-01 2011-03-01 Chugai Seiyaku Kabushiki Kaisha Compuestos heterocíclicos útiles como inhibidores de la malonil-coa-descarboxilasa.
WO2005011693A1 (en) 2003-08-01 2005-02-10 Chugai Seiyaku Kabushiki Kaisha Piperidine compounds useful as malonyl-coa decarboxylase inhibitors
EP2208495B1 (de) 2003-08-01 2011-12-14 Chugai Seiyaku Kabushiki Kaisha Azol-Verbindungen auf Cyanoguanidin-Basis als Malonyl-Coa Decarboxylase-Hemmer
US7452909B2 (en) * 2003-09-04 2008-11-18 Hoffman-La Roche Inc. Imidazole derivatives
JP4690395B2 (ja) 2004-06-01 2011-06-01 エフ．ホフマン−ラ ロシュ アーゲー ｍＧｌｕ５レセプターアンタゴニストとしてのピリジン−４−エチニル−イミダゾール及びピラゾール
AU2005277138A1 (en) 2004-08-23 2006-03-02 Wyeth Holdings Corporation Oxazolo-naphthyl acids as plaminogen activator inhibtor type-1 (PAI-1) modulators useful in the treatment of thrombosis and cardiovascular diseases
EP1781641A1 (de) 2004-08-23 2007-05-09 Wyeth Pyrrolo-naphthyl-säuren als pai-1 hemmer
CN101044127A (zh) 2004-08-23 2007-09-26 惠氏公司 用作纤溶酶原激活剂抑制剂－1的噻唑基－萘基酸
JP5405311B2 (ja) 2006-12-21 2014-02-05 エフ．ホフマン−ラ ロシュ アーゲー ｍＧｌｕＲ５受容体アンタゴニストの多形
US8034782B2 (en) 2008-07-16 2011-10-11 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
EA020466B1 (ru) 2007-06-04 2014-11-28 Синерджи Фармасьютикалз Инк. Агонисты гуанилатциклазы, пригодные для лечения желудочно-кишечных нарушений, воспаления, рака и других заболеваний
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
EP2810951B1 (de) 2008-06-04 2017-03-15 Synergy Pharmaceuticals Inc. Für die Behandlung von gastrointestinalen Erkrankungen, Entzündungen, Krebs und anderen Erkrankungen geeignete Agonisten von Guanylatcyclase
US20120264753A1 (en) * 2009-12-22 2012-10-18 Kowa Company, Ltd. Novel 1-(biphenyl-4-yl-methyl)-1h-imidazole derivative and pharmaceutical product containing same
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
EP2970384A1 (de) 2013-03-15 2016-01-20 Synergy Pharmaceuticals Inc. Agonisten der guanylatcyclase und deren verwendungen
US9486494B2 (en) 2013-03-15 2016-11-08 Synergy Pharmaceuticals, Inc. Compositions useful for the treatment of gastrointestinal disorders
CN105764916B (zh) 2013-06-05 2021-05-18 博士医疗爱尔兰有限公司 鸟苷酸环化酶c的超纯激动剂、制备和使用所述激动剂的方法
KR102319263B1 (ko) 2017-11-30 2021-10-29 주식회사 엘지화학 방열 유체 조성물, 이의 제조방법, 이를 포함하는 전지 모듈 및 배터리 팩

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6323868A (ja) * 1986-07-11 1988-02-01 イー・アイ・デュポン・ドゥ・ヌムール・アンド・カンパニー アンギオテンシン２受容体遮断性イミダゾ−ル
CA1334092C (en) * 1986-07-11 1995-01-24 David John Carini Angiotensin ii receptor blocking imidazoles
CA1338238C (en) * 1988-01-07 1996-04-09 David John Carini Angiotensin ii receptor blocking imidazoles and combinations thereof with diuretics and nsaids

Also Published As

Publication number Publication date
KR920702681A (ko) 1992-10-06
JP2550442B2 (ja) 1996-11-06
FI916129A0 (fi) 1991-12-27
DK0479903T3 (da) 1996-03-18
NO915113D0 (no) 1991-12-27
AU644802B2 (en) 1993-12-23
DE69025473T2 (de) 1996-10-17
ES2084702T3 (es) 1996-05-16
KR0163595B1 (ko) 1998-12-01
JPH04506522A (ja) 1992-11-12
AU5957990A (en) 1991-01-17
DE69025473D1 (de) 1996-03-28
RU2099330C1 (ru) 1997-12-20
ATE134368T1 (de) 1996-03-15
HU217958B (hu) 2000-05-28
CA2060656A1 (en) 1990-12-31
NO915113L (no) 1992-02-28
EP0479903A1 (de) 1992-04-15
HUT62575A (en) 1993-05-28
WO1991000277A1 (en) 1991-01-10
HU905605D0 (en) 1992-06-29
SG52709A1 (en) 1998-09-28

Similar Documents

Publication Publication Date Title
EP0479903B1 (de) Substituierte imidazole und ihre verwendung als hemmmstoff fur angiotensin ii
JP2568315B2 (ja) 縮合環アリール置換イミダゾール
EP0324377B1 (de) Angiotensin-II-Rezeptor blockende Imidazole und deren Kombinationen mit Diuretica und NSAids
KR900005045B1 (ko) 앤지오텐신 ii수용체 차단 이미다졸
JPH0529351B2 (de)
US5354867A (en) Angiotensin II receptor blocking imidazoles
EP0733366B1 (de) Angiotensin II-Rezeptor blockierende Imidazole und Diuretika enthaltende pharmazeutische Zusammensetzungen
IL95259A (en) Substituted n-aryl and -aralkyl-imidazoles, their preparation and pharmaceutical compositions containing them.
IL95258A (en) Substituted imidazoles, their preparation and pharmaceutical compositions containing them
PT95127B (pt) Processo para a preparacao de compostos imidazolicos comportando como substituintes nucleos arilicos condensados com accao bloqueadora da angiotensina ii e de composicoes farmaceuticas que os contem
PT95126B (pt) Processo para a preparacao de compostos imidazolicos substituidos com accao bloqueadora da angiotensina ii e de composicoes farmaceuticas que os contem
HU211674A9 (hu) Az átmeneti oltalom az 1-39. igénypontokra vonatkozik.
HU218201B (hu) Eljárás angiotenzin II receptor blokkoló imidazol-származékok, valamint ezeket tartalmazó gyógyászati készítmények előállítására

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19911218

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB IT LI LU NL SE

17Q First examination report despatched

Effective date: 19930914

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE PATENT HAS BEEN GRANTED

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH DE DK ES FR GB IT LI LU NL SE

REF Corresponds to:

Ref document number: 134368

Country of ref document: AT

Date of ref document: 19960315

Kind code of ref document: T

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

REF Corresponds to:

Ref document number: 69025473

Country of ref document: DE

Date of ref document: 19960328

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: PATENTANWALTSBUREAU R. A. MASPOLI

ET Fr: translation filed
ITF It: translation for a ep patent filed
REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2084702

Country of ref document: ES

Kind code of ref document: T3

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

26N No opposition filed
PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 19990226

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DK

Payment date: 19990301

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 19990302

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 19990305

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 19990308

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 19990311

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 19990326

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 19990328

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 19990503

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 19990607

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 19990621

Year of fee payment: 10

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF THE APPLICANT RENOUNCES

Effective date: 19990728

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20000628

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20000628

Ref country code: DK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20000628

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20000628

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20000629

Ref country code: ES

Free format text: THE PATENT HAS BEEN ANNULLED BY A DECISION OF A NATIONAL AUTHORITY

Effective date: 20000629

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20000630

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20000630

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20000630

BERE Be: lapsed

Owner name: E.I. DU PONT DE NEMOURS AND CY

Effective date: 20000630

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20010101

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20000628

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

EUG Se: european patent has lapsed

Ref document number: 90911154.4

REG Reference to a national code

Ref country code: DK

Ref legal event code: EBP

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20010228

NLV4 Nl: lapsed or anulled due to non-payment of the annual fee

Effective date: 20010101

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20020304

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES;WARNING: LAPSES OF ITALIAN PATENTS WITH EFFECTIVE DATE BEFORE 2007 MAY HAVE OCCURRED AT ANY TIME BEFORE 2007. THE CORRECT EFFECTIVE DATE MAY BE DIFFERENT FROM THE ONE RECORDED.

Effective date: 20050628